https://wiki.oroboros.at/api.php?action=feedcontributions&user=Krumschnabel+Gerhard&feedformat=atom
Bioblast - User contributions [en]
2024-03-29T06:07:00Z
User contributions
MediaWiki 1.36.1
https://wiki.oroboros.at/index.php?title=Haschka_2018_Mov_Disord&diff=184489
Haschka 2018 Mov Disord
2019-08-16T11:56:26Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Haschka D, Volani C, Stefani A, Tymoszuk P, Mitterling T, Holzknecht E, Heidbreder A, Coassin S, Sumbalova Z, Seifert M, Dichtl S, Theurl I, Gnaiger E, Kronenberg F, Frauscher B, Högl B, Weiss G (2018) Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome. Mov Disord 34:114-23.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30311259 PMID: 30311259]<br />
|authors=Haschka D, Volani C, Stefani A, Tymoszuk P, Mitterling T, Holzknecht E, Heidbreder A, Coassin S, Sumbalova Z, Seifert M, Dichtl S, Theurl I, Gnaiger E, Kronenberg F, Frauscher B, Högl B, Weiss G<br />
|year=2018<br />
|journal=Mov Disord<br />
|abstract=Restless legs syndrome is a sensorimotor neurological disorder of the limbs that impairs quality of life and disturbs sleep. However, there has been progress in understanding the disease involving the dopaminergic system as well as iron metabolism. The exact pathophysiological mechanisms of restless legs syndrome remain elusive. We tried to elucidate the underlying mechanisms in iron metabolism in restless legs syndrome subjects on a systemic, cellular, and mitochondrial level.<br />
<br />
We conducted a study prospectively recruiting 168 restless legs syndrome patients and 119 age-matched healthy controls focusing on iron metabolism using human monocytes as surrogates.<br />
<br />
Evaluation of systemic iron metabolism parameters in the circulation showed no significant difference between patients and controls. We observed a significant reduction in mRNA levels of heme oxygenase 1 and mitochondrial iron genes like mitoferrin 1 and 2 in monocytes isolated from restless legs syndrome patients, indicating mitochondrial iron deficiency. Interestingly, we also observed reduced expression of iron regulatory protein 2 along with impaired activity of mitochondrial aconitase and reduced mitochondrial superoxide formation in restless legs syndrome subjects. Along this line, patients had reduced mitochondrial respiratory capacity that improved in restless legs syndrome subjects under treatment with dopaminergic drugs compared with untreated patients.<br />
<br />
Our data suggest that restless legs syndrome is linked to mitochondrial iron deficiency and associated impairment of mitochondrial function. This is partly corrected by treatment with dopaminergic drugs compared with untreated patients, which may be linked to an effect of dopamine on cellular iron homeostasis.<br />
<br />
<small>© 2018 International Parkinson and Movement Disorder Society.</small><br />
|keywords=Willis-Ekbom disease, Iron, Mitochondria, Pathophysiology, Restless legs syndrome<br />
|editor=[[Plangger M]],<br />
|mipnetlab=AT Innsbruck Oroboros, SK Bratislava Sumbalova Z, AT Innsbruck Gnaiger E<br />
}}<br />
{{Labeling<br />
|area=Respiration, mt-Medicine<br />
|diseases=Other<br />
|organism=Human<br />
|tissues=Blood cells, Lymphocyte<br />
|preparations=Intact cells<br />
|couplingstates=LEAK, ROUTINE, ET<br />
|pathways=ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2018-10, PBMCs,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Sansone_2017_Proc_Natl_Acad_Sci_U_S_A&diff=184488
Sansone 2017 Proc Natl Acad Sci U S A
2019-08-16T11:51:13Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Sansone P, Savini C, Kurelac I, Chang Q, Amato LB, Strillacci A, Stepanova A, Iommarini L, Mastroleo C, Daly L, Galkin A, Thakur BK, Soplop N, Uryu K, Hoshino A, Norton L, Bonafé M, Cricca M, Gasparre G, Lyden D, Bromberg J (2017) Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc Natl Acad Sci U S A 114:E9066-75.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/29073103 PMID: 29073103 Open Access]<br />
|authors=Sansone P, Savini C, Kurelac I, Chang Q, Amato LB, Strillacci A, Stepanova A, Iommarini L, Mastroleo C, Daly L, Galkin A, Thakur BK, Soplop N, Uryu K, Hoshino A, Norton L, Bonafe M, Cricca M, Gasparre G, Lyden D, Bromberg J<br />
|year=2017<br />
|journal=Proc Natl Acad Sci U S A<br />
|abstract=The horizontal transfer of mtDNA and its role in mediating resistance to therapy and an exit from dormancy have never been investigated. Here we identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal therapy-resistant (HTR) metastatic breast cancer. We generated xenograft models of HTR metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HTR cells had acquired host-derived (murine) mtDNA promoting estrogen receptor-independent oxidative phosphorylation (OXPHOS). Functional studies identified cancer-associated fibroblast (CAF)-derived EVs (from patients and xenograft models) laden with whole genomic mtDNA as a mediator of this phenotype. Specifically, the treatment of hormone therapy (HT)-naive cells or HT-treated metabolically dormant populations with CAF-derived mtDNAhi EVs promoted an escape from metabolic quiescence and HTR disease both in vitro and in vivo. Moreover, this phenotype was associated with the acquisition of EV mtDNA, especially in cancer stem-like cells, expression of EV mtRNA, and restoration of OXPHOS. In summary, we have demonstrated that the horizontal transfer of mtDNA from EVs acts as an oncogenic signal promoting an exit from dormancy of therapy-induced cancer stem-like cells and leading to endocrine therapy resistance in OXPHOS-dependent breast cancer.<br />
|keywords=Cancer stem cells, Exosomes, Hormonal therapy, Metastasis, Mitochondrial DNA<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US NY New York Galkin A<br />
}}<br />
{{Labeling<br />
|area=Respiration, mtDNA;mt-genetics<br />
|diseases=Cancer<br />
|organism=Human<br />
|couplingstates=LEAK, OXPHOS<br />
|additional=2018-10,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Ramos_2019_Am_J_Physiol_Cell_Physiol&diff=184487
Ramos 2019 Am J Physiol Cell Physiol
2019-08-16T11:47:13Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Ramos SV, Hughes MC, Perry CGR (2019) Altered skeletal muscle microtubule-mitochondrial VDAC2 binding is related to bioenergetic impairments after paclitaxel but not vinblastine chemotherapies. Am J Physiol Cell Physiol 316:C449-C455.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30624982 PMID: 30624982]<br />
|authors=Ramos SV, Hughes MC, Perry CGR<br />
|year=2019<br />
|journal=Am J Physiol Cell Physiol<br />
|abstract=Microtubule-targeting chemotherapies are linked to impaired cellular metabolism which may contribute to skeletal muscle dysfunction. However, the mechanisms by which metabolic homeostasis is perturbed remains unknown. Tubulin, the fundamental unit of microtubules, has been implicated in the regulation of mitochondrial-cytosolic ADP/ATP exchange through its interaction with the outer membrane voltage-dependent anion channel (VDAC). Based on this model, we predicted that disrupting microtubule architecture with the stabilizer paclitaxel and destabilizer vinblastine would impair skeletal muscle mitochondrial bioenergetics. Here we provide ''in vitro'' evidence of a direct interaction between both a-tubulin and bII-tubulin with VDAC2 in un-treated single ''extensor digitorum longus'' fibres. Paclitaxel increased both a- and bII-tubulin-VDAC2 interactions whereas vinblastine had no effect. Utilizing a permeabilized muscle fiber bundle preparation that retains the cytoskeleton, paclitaxel treatment impaired the ability of ADP to attenuate H<sub>2</sub>O<sub>2</sub> emission, resulting in greater H<sub>2</sub>O<sub>2</sub> emission kinetics. Despite no effect on tubulin-VDAC2 binding, vinblastine still altered mitochondrial bioenergetics through a surprising increase in ADP-stimulated respiration while also impairing ADP-suppression of H<sub>2</sub>O<sub>2</sub> and increasing mitochondrial susceptibility to calcium-induced formation of the pro-apoptotic permeability transition pore. Collectively, these results demonstrate that altering microtubule architecture with chemotherapeutics disrupts mitochondrial bioenergetics in skeletal muscle. Altered tubulin-VDAC binding with paclitaxel supports the model that microtubules regulate mitochondria by altering ADP's governance of bioenergetics, whereas vinblastine may act through an alternative mechanism associated with decreased microtubule abundance in skeletal muscle.<br />
|keywords=Chemotherapy, Microtubule, Mitochondria, Paclitaxel, Vinblastine, Blebbistatin<br />
|editor=[[Plangger M]],<br />
|mipnetlab=CA Toronto Perry CG<br />
}}<br />
{{Labeling<br />
|area=Respiration, Pharmacology;toxicology<br />
|organism=Rat<br />
|tissues=Skeletal muscle<br />
|preparations=Permeabilized tissue<br />
|couplingstates=OXPHOS<br />
|pathways=N<br />
|instruments=Oxygraph-2k<br />
|additional=2019-02,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Jeon_2019_Sci_Rep&diff=184486
Jeon 2019 Sci Rep
2019-08-16T11:44:12Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Jeon AB, Ackart DF, Li W, Jackson M, Melander RJ, Melander C, Abramovitch RB, Chicco AJ, Basaraba RJ, Obregón-Henao A (2019) 2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain. Sci Rep 9:1513.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30728417 PMID: 30728417 Open Access]<br />
|authors=Jeon AB, Ackart DF, Li W, Jackson M, Melander RJ, Melander C, Abramovitch RB, Chicco AJ, Basaraba RJ, Obregon-Henao A<br />
|year=2019<br />
|journal=Sci Rep<br />
|abstract=There is an urgent need to develop new drugs against tuberculosis. In particular, it is critical to target drug tolerant ''Mycobacterium tuberculosis'' (''M. tuberculosis''), responsible, in part, for the lengthy antibiotic regimen required for treatment. We previously postulated that the presence of ''in vivo'' biofilm-like communities of ''M. tuberculosis'' could contribute to this drug tolerance. Consistent with this hypothesis, certain 2-aminoimidazole (2-AIs) molecules with anti-biofilm activity were shown to revert mycobacterial drug tolerance in an ''in vitro M. tuberculosis'' biofilm model. While exploring their mechanism of action, it was serendipitously observed that these 2-AI molecules also potentiated β-lactam antibiotics by affecting mycobacterial protein secretion and lipid export. As these two bacterial processes are energy-dependent, herein it was evaluated if 2-AI compounds affect mycobacterial bioenergetics. At low concentrations, 2B8, the lead 2-AI compound, collapsed both components of the proton motive force, similar to other cationic amphiphiles. Interestingly, however, the minimum inhibitory concentration of 2B8 against ''M. tuberculosis'' correlated with a higher drug concentration determined to interfere with the mycobacterial electron transport chain. Collectively, this study elucidates the mechanism of action of 2-AIs against ''M. tuberculosis'', providing a tool to better understand mycobacterial bioenergetics and develop compounds with improved anti-mycobacterial activity.<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US CO Fort Collins Chicco AJ<br />
}}<br />
{{Labeling<br />
|area=Respiration, Pharmacology;toxicology<br />
|diseases=Infectious<br />
|organism=Eubacteria<br />
|preparations=Intact cells<br />
|couplingstates=ROUTINE<br />
|instruments=Oxygraph-2k<br />
|additional=2019-02,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Woodman_2019_Cardiovasc_Res&diff=184485
Woodman 2019 Cardiovasc Res
2019-08-16T11:38:43Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Woodman AG, Mah R, Keddie DL, Noble RMN, Holody CD, Panahi S, Gragasin FS, Lemieux H, Bourque SL (2019) Perinatal iron deficiency and a high salt diet cause long-term kidney mitochondrial dysfunction and oxidative stress. Cardiovasc Res [Epub ahead of print].<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30715197 PMID: 30715197]<br />
|authors=Woodman AG, Mah R, Keddie DL, Noble RMN, Holody CD, Panahi S, Gragasin FS, Lemieux H, Bourque SL<br />
|year=2019<br />
|journal=Cardiovasc Res<br />
|abstract=Perinatal iron deficiency alters developmental trajectories of offspring, predisposing them to cardiovascular dysfunction in later life. The mechanisms underlying this long-term programming of renal function have not been defined. We hypothesized perinatal iron deficiency causes hypertension and alters kidney metabolic function and morphology in a sex-dependent manner in adult offspring. Furthermore, we hypothesized these effects are exacerbated by chronic consumption of a high salt diet.<br />
<br />
Pregnant Sprague Dawley rats were fed either an iron-restricted or replete diet prior to and throughout pregnancy. Adult offspring were fed normal or high salt diets for six weeks prior to experimentation at six months of age. Blood pressure was assessed via indwelling catheters in anesthetized offspring; kidney mitochondrial function was assessed via high-resolution respirometry; reactive oxygen species and nitric oxide were quantified via fluorescence microscopy. Adult males, but not females, exhibited increased systolic blood pressure due to iron deficiency (P = 0.01) and high salt intake (P = 0.02). In males, but not in females, medullary mitochondrial content was increased by high salt (P = 0.003), while succinate-dependent respiration was reduced by iron deficiency (P < 0.05). The combination of perinatal iron deficiency and high salt reduced complex IV activity in the cortex of males (P = 0.01). Perinatal iron deficiency increased cytosolic superoxide generation (P < 0.001) concomitant with reduced nitric oxide bioavailability (P < 0.001) in male offspring, while high salt increased mitochondrial superoxide in the medulla (P = 0.04) and cytosolic superoxide within the cortex (P = 0.01). Male offspring exhibited glomerular basement membrane thickening (P < 0.05), increased collagen deposition (P < 0.05), and glomerular hypertrophy (interaction, P = 0.02) due to both perinatal iron deficiency and high salt. Female offspring exhibited no alterations in mitochondrial function or morphology due to either high salt or iron deficiency.<br />
<br />
Perinatal iron deficiency causes long-term sex-dependent alterations in renal metabolic function and morphology, potentially contributing to hypertension and increased cardiovascular disease risk.<br />
|keywords=Anaemia, Developmental programming, Hypertension, Mitochondria, Nitric oxide, Pregnancy, Renal<br />
|editor=[[Plangger M]],<br />
|mipnetlab=CA Edmonton Lemieux H<br />
}}<br />
{{Labeling<br />
|area=Respiration, Gender, Developmental biology, Exercise physiology;nutrition;life style<br />
|diseases=Other<br />
|organism=Rat<br />
|tissues=Kidney<br />
|preparations=Homogenate<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=N, S, CIV, NS<br />
|instruments=Oxygraph-2k<br />
|additional=2019-02,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Gregg_2019_J_Biol_Chem&diff=184484
Gregg 2019 J Biol Chem
2019-08-16T11:18:05Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Gregg T, Sdao SM, Dhillon RS, Rensvold JW, Lewandowski SL, Pagliarini DJ, Denu JM, Merrins MJ (2019) Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic β-cells. J Biol Chem 294:4656-66.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30700550 PMID: 30700550 Open Access]<br />
|authors=Gregg T, Sdao SM, Dhillon RS, Rensvold JW, Lewandowski SL, Pagliarini DJ, Denu JM, Merrins MJ<br />
|year=2019<br />
|journal=J Biol Chem<br />
|abstract=β-cell mitochondria play a central role in coupling glucose metabolism with insulin secretion. Here, we identified a metabolic function of cyclin-dependent kinase 1 (CDK1)/cyclin B1 - the activation of mitochondrial respiratory complex I - that is active in quiescent adult β-cells and hyperactive in β-cells from obese (''ob/ob'') mice. In wild-type islets, respirometry revealed that 65% of complex I flux and 49% of state 3 respiration is sensitive to CDK1 inhibition. Islets from ''ob/ob'' mice expressed more cyclin B1 and exhibited a higher sensitivity to CDK1 blockade, which reduced complex I flux by 76% and state 3 respiration by 79%. The ensuing reduction in mitochondrial NADH utilization, measured with 2-photon NAD(P)H fluorescence lifetime imaging (FLIM), was matched in the cytosol by a lag in citrate cycling, as shown with a FRET reporter targeted to β-cells. Moreover, time-resolved measurements revealed that in ''ob/ob'' islets, where complex I flux dominates respiration, CDK1 inhibition is sufficient to restrict the duty cycle of ATP/ADP and calcium oscillations, the parameter that dynamically encodes β-cell glucose sensing. Direct complex I inhibition with rotenone mimicked the restrictive effects of CDK1 inhibition on mitochondrial respiration, NADH turnover, ATP/ADP, and calcium influx. These findings identify complex I as a critical mediator of obesity-associated metabolic remodeling in β-cells, and implicate CDK1 as a regulator of complex I that enhances β-cell glucose sensing.<br />
<br />
</small>Published under license by The American Society for Biochemistry and Molecular Biology, Inc.</small><br />
|keywords=Complex I, RO-3306, Calcium, Cyclin B1, Cyclin-dependent kinase 1 (CDK1), Insulin secretion, Mitochondrial metabolism, ob/ob mice, Obesity, Pancreatic beta cell<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US WI Madison Denu JM<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|diseases=Diabetes, Obesity<br />
|organism=Mouse<br />
|tissues=Islet cell;pancreas;thymus<br />
|preparations=Permeabilized tissue<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=N, S, NS, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-02,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Urazov_2018_Sovrem_Tekhnologii_Med&diff=184483
Urazov 2018 Sovrem Tekhnologii Med
2019-08-16T11:11:05Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Urazov MD, Astrakhanova TA, Usenko AV, Mishchenko TA, Schelchkova NA, Kravchenko GA, Vedunova MV, Mitroshina EV (2018) New aspects of central nervous system adaptation to prenatal hypoxia. Sovrem Tekhnologii Med 10:60-68.<br />
|info=[http://stm-journal.ru/en/numbers/2018/4/1476 Open Access]<br />
|authors=Urazov MD, Astrakhanova TA, Usenko AV, Mishchenko TA, Schelchkova NA, Kravchenko GA, Vedunova MV, Mitroshina EV<br />
|year=2018<br />
|journal=Sovrem Tekhnologii Med<br />
|abstract=The aim of the investigation was to study the effect of chronic and acute prenatal hypoxia on the parameters of CNS functional activity and to assess the role of mitochondria in the protection of the CNS against experimental hypoxic influence ''in vivo''.<br />
<br />
The experiments ''in vivo'' were performed on C57BL/6 mice. In order to model chronic prenatal hypoxia, pregnant female mice were placed daily into a hypobaric chamber beginning with the fourteenth day of gestation up to delivery. 280–300 mm Hg pressure corresponding to the altitude of 8000 m above sea level was maintained in the chamber for 2 h. Acute prenatal hypoxia was modeled on the eighteenth day of gestation. Pregnant females were placed for 4–5 min (till the first agonal breath) in the hypobaric chamber under 220–240 mm Hg pressure corresponding to the altitude of 10,000 m above sea level.<br />
<br />
Oxygen consumption rate by mice brain mitochondria was assessed on the first day of the post-natal period using a high-resolution Oxygraph-2k respirometer (Oroboros Instruments, Austria). To determine a general state of the CNS in the remote post-hypoxic period, a neurological status of the 4-week-old animals was evaluated according to the neurological deficit scale for small laboratory animals and Garcia’s scale. Mnestic and cognitive abilities were also tested in Morris water maze.<br />
<br />
Protocols of acute and chronic prenatal hypoxia modeling for mice have been designed. Acute hypoxic damage has been shown to result in the significant decrease of the basal oxygen consumption rate and intensity of oxidative phosphorylation by the brain mitochondria of the newborn mice, and in the activation of the respiratory complex II. After chronic prenatal hypoxia, the basal oxygen consumption rate and oxidative phosphorylation intensity significantly increased relative to the intact group.<br />
<br />
The designed protocols of experimental prenatal hypoxia modeling allowed us to reveal a specific pattern of mitochondrial apparatus adaptation to various types of hypoxic damage. Chronic hypoxia leads to adaptation of the mitochondrial apparatus characterized by intensification of oxidative phosphorylation.<br />
|keywords=Prenatal hypoxia, Oxidative phosphorylation, Mitochondria, CNS<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|injuries=Hypoxia<br />
|organism=Mouse<br />
|tissues=Nervous system<br />
|preparations=Isolated mitochondria<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N, S, NS<br />
|instruments=Oxygraph-2k<br />
|additional=2019-02,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Malagrino_2019_Oxid_Med_Cell_Longev&diff=184479
Malagrino 2019 Oxid Med Cell Longev
2019-08-16T10:05:20Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Malagrinò F, Zuhra K, Mascolo L, Mastronicola D, Vicente JB, Forte E, Giuffrè A (2019) Hydrogen sulfide oxidation: adaptive changes in mitochondria of SW480 colorectal cancer cells upon exposure to hypoxia. Oxid Med Cell Longev 2019:8102936.<br />
|info=[https://www.hindawi.com/journals/omcl/2019/8102936/ Open Access]<br />
|authors=Malagrino F, Zuhra K, Mascolo L, Mastronicola D, Vicente JB, Forte E, Giuffre A<br />
|year=2019<br />
|journal=Oxid Med Cell Longev<br />
|abstract=Hydrogen sulfide (H<sub>2</sub>S), a known inhibitor of cytochrome c oxidase (CcOX), plays a key signaling role in human (patho)physiology. H<sub>2</sub>S is synthesized endogenously and mainly metabolized by a mitochondrial sulfide-oxidizing pathway including sulfide:quinone oxidoreductase (SQR), whereby H<sub>2</sub>S-derived electrons are injected into the respiratory chain stimulating O<sub>2</sub> consumption and ATP synthesis. Under hypoxic conditions, H<sub>2</sub>S has higher stability and is synthesized at higher levels with protective effects for the cell. Herein, working on SW480 colon cancer cells, we evaluated the effect of hypoxia on the ability of cells to metabolize H<sub>2</sub>S. The sulfide-oxidizing activity was assessed by high-resolution respirometry, measuring the stimulatory effect of sulfide on rotenone-inhibited cell respiration in the absence or presence of antimycin A. Compared to cells grown under normoxic conditions (air O<sub>2</sub>), cells exposed for 24 h to hypoxia (1% O<sub>2</sub>) displayed a 1.3-fold reduction in maximal sulfide-oxidizing activity and 2.7-fold lower basal O<sub>2</sub> respiration. Based on citrate synthase activity assays, mitochondria of hypoxia-treated cells were 1.8-fold less abundant and displayed 1.4-fold higher maximal sulfide-oxidizing activity and 2.6-fold enrichment in SQR as evaluated by immunoblotting. We speculate that under hypoxic conditions mitochondria undergo these adaptive changes to protect cell respiration from H<sub>2</sub>S poisoning.<br />
|keywords=H2S-oxidizing activity<br />
|editor=[[Plangger M]],<br />
|mipnetlab=IT Roma Sarti P<br />
}}<br />
{{Labeling<br />
|area=Respiration, Pharmacology;toxicology<br />
|diseases=Cancer<br />
|injuries=Hypoxia<br />
|organism=Human<br />
|tissues=Endothelial;epithelial;mesothelial cell<br />
|preparations=Intact cells<br />
|topics=Inhibitor<br />
|couplingstates=ROUTINE<br />
|pathways=ROX<br />
|instruments=Oxygraph-2k, TIP2k<br />
|additional=2019-02,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Maresch_2019_Hepatol_Commun&diff=184477
Maresch 2019 Hepatol Commun
2019-08-16T10:01:25Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Maresch LK, Benedikt P, Feiler U, Eder S, Zierler KA, Taschler U, Kolleritsch S, Eichmann TO, Schoiswohl G, Leopold C, Wieser B, Lackner C, Rülicke T, van Klinken J, Kratky D, Moustafa T, Hoefler G, Haemmerle G (2019) Intestine‐specific overexpression of carboxylesterase 2c protects mice from diet‐induced liver steatosis and obesity. Hepatol Commun 3:227-45.<br />
|info=[https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.1292 Open Access]<br />
|authors=Maresch LK, Benedikt P, Feiler U, Eder S, Zierler KA, Taschler U, Kolleritsch S, Eichmann TO, Schoiswohl G, Leopold C, Wieser B, Lackner C, Ruelicke T, van Klinken J, Kratky D, Moustafa T, Hoefler G, Haemmerle G<br />
|year=2019<br />
|journal=Hepatol Commun<br />
|abstract=Murine hepatic carboxylesterase 2c (''Ces2c'') and the presumed human ortholog carboxylesterase 2 (CES2) have been implicated in the development of nonalcoholic fatty liver disease (NAFLD) in mice and obese humans. These studies demonstrated that ''Ces2c'' hydrolyzes triglycerides (TGs) in hepatocytes. Interestingly, ''Ces2c/CES2'' is most abundantly expressed in the intestine, indicating a role of ''Ces2c/CES2'' in intestinal TG metabolism. Here we show that ''Ces2c'' is an important enzyme in intestinal lipid metabolism in mice. Intestine‐specific ''Ces2c'' overexpression (Ces2c<sup>int</sup>) provoked increased fatty acid oxidation (FAO) in the small intestine accompanied by enhanced chylomicron clearance from the circulation. As a consequence, high‐fat diet–fed Ces2c<sup>int</sup> mice were resistant to excessive diet‐induced weight gain and adipose tissue expansion. Notably, intestinal ''Ces2c'' overexpression increased hepatic insulin sensitivity and protected mice from NAFLD development. Although lipid absorption was not affected in Ces2c<sup>int</sup> mice, fecal energy content was significantly increased. Mechanistically, we demonstrate that ''Ces2c'' is a potent neutral lipase, which efficiently hydrolyzes TGs and diglycerides (DGs) in the small intestine, thereby generating fatty acids (FAs) for FAO and monoglycerides (MGs) and DGs for potential re‐esterification. Consequently, the increased availability of MGs and DGs for re‐esterification and primordial apolipoprotein B48 particle lipidation may increase chylomicron size, ultimately mediating more efficient chylomicron clearance from the circulation. <br />
<br />
This study suggests a critical role for ''Ces2c'' in intestinal lipid metabolism and highlights the importance of intestinal lipolysis to protect mice from the development of hepatic insulin resistance, NAFLD, and excessive diet‐induced weight gain during metabolic stress.<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, nDNA;cell genetics, Exercise physiology;nutrition;life style<br />
|organism=Mouse<br />
|tissues=Endothelial;epithelial;mesothelial cell<br />
|preparations=Homogenate<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=F<br />
|instruments=Oxygraph-2k<br />
|additional=2019-02,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Anderson_2019_Acta_Neuropathol&diff=184474
Anderson 2019 Acta Neuropathol
2019-08-16T09:32:05Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Anderson CJ, Bredvik K, Burstein SR, Davis C, Meadows SM, Dash J, Case L, Milner TA, Kawamata H, Zuberi A, Piersigilli A, Lutz C, Manfredi G (2019) ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response. Acta Neuropathol 138:103-21.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30877432 PMID: 30877432]<br />
|authors=Anderson CJ, Bredvik K, Burstein SR, Davis C, Meadows SM, Dash J, Case L, Milner TA, Kawamata H, Zuberi A, Piersigilli A, Lutz C, Manfredi G<br />
|year=2019<br />
|journal=Acta Neuropathol<br />
|abstract=Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice harboring the mouse-equivalent of a disease-associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10<sup>S55L</sup> mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10<sup>S55L</sup> mice, leading to aberrant organelle morphology and function. Aggregates induce a potent mitochondrial integrated stress response (mtISR) through mTORC1 activation, with elevation of stress-induced transcription factors, secretion of myokines, upregulated serine and one-carbon metabolism, and downregulation of respiratory chain enzymes. Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10<sup>S55L</sup>-dependent disease pathology is not caused by loss-of-function. Overall, CHCHD10<sup>S55L</sup> mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation.<br />
|keywords=ALS, CHCHD10, CHCHD2, FTD, Knock-in mice, Mitochondrial integrated stress response, Mitochondrial myopathy, Neurodegeneration, Protein aggregation<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, nDNA;cell genetics, Genetic knockout;overexpression<br />
|diseases=Myopathy, Neurodegenerative<br />
|organism=Mouse<br />
|tissues=Heart<br />
|preparations=Isolated mitochondria<br />
|couplingstates=LEAK<br />
|pathways=N, S<br />
|instruments=Oxygraph-2k<br />
|additional=2019-03,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Rojas-Morales_2019_Free_Radic_Biol_Med&diff=184473
Rojas-Morales 2019 Free Radic Biol Med
2019-08-16T09:28:02Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Rojas-Morales P, León-Contreras JC, Aparicio-Trejo OE, Reyes- Ocampo JG, Medina-Campos ON, Jiménez-Osorio AS, González-Reyes S, Marquina- Castillo B, Hernández-Pando R, Barrera-Oviedo D, Sánchez-Lozada LG, Pedraza-Chaverri J, Tapia E (2019) Fasting reduces oxidative stress, mitochondrial dysfunction and fibrosis induced by renal ischemia-reperfusion injury. Free Radic Biol Med 135:60-67.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30818054 PMID: 30818054]<br />
|authors=Rojas-Morales P, Leon-Contreras JC, Aparicio-Trejo OE, Reyes- Ocampo JG, Medina-Campos ON, Jimenez-Osorio AS, Gonzalez-Reyes S, Marquina-Castillo B, Hernandez-Pando R, Barrera-Oviedo D, Sanchez-Lozada LG, Pedraza-Chaverri J, Tapia E<br />
|year=2019<br />
|journal=Free Radic Biol Med<br />
|abstract=Food deprivation protects against ischemia-reperfusion (IR) injury through unknown mechanisms. In an experimental rat model of acute IR injury, we found that preoperative fasting for 3 days protects rats from tubular damage and renal functional decline by increasing antioxidant protection independently of the NF-E2-related factor 2 (Nrf2), and by maintaining mitochondrial morphology and function. In addition, further analysis revealed that fasting protects against tubulointerstitial fibrosis. In summary, our results point out to fasting as a robust nutritional intervention to limit oxidative stress and mitochondrial dysfunction in early acute kidney injury and also to promote long-term protection against fibrosis.<br />
|keywords=Fasting, Oxidative stress, Mitochondrial dysfunction, Fibrosis, Ischemia-reperfusion injury, Acute kidney injury, Chronic kidney disease<br />
|editor=[[Plangger M]],<br />
|mipnetlab=MX Mexico City Pedraza Chaverri J<br />
}}<br />
{{Labeling<br />
|area=Respiration, Exercise physiology;nutrition;life style<br />
|injuries=Ischemia-reperfusion, Oxidative stress;RONS<br />
|organism=Rat<br />
|tissues=Kidney<br />
|preparations=Isolated mitochondria<br />
|topics=mt-Membrane potential<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N<br />
|instruments=Oxygraph-2k, O2k-Fluorometer<br />
|additional=2019-02, Safranin,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Porter_2017_Adipocyte&diff=184469
Porter 2017 Adipocyte
2019-08-16T08:37:28Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Porter C (2017) Quantification of UCP1 function in human brown adipose tissue. Adipocyte 6:167-74.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/28453364 PMID: 28453364 Open Access]<br />
|authors=Porter C<br />
|year=2017<br />
|journal=Adipocyte<br />
|abstract=Brown adipose tissue (BAT) mitochondria are distinct from their counterparts in other tissues in that ATP production is not their primary physiologic role. BAT mitochondria are equipped with a specialized protein known as uncoupling protein 1 (UCP1). UCP1 short-circuits the electron transport chain, allowing mitochondrial membrane potential to be transduced to heat, making BAT a tissue capable of altering energy expenditure and fuel metabolism in mammals without increasing physical activity. <br />
<br />
The recent discovery that adult humans have metabolically active BAT has rekindled an interest in this intriguing tissue, with the overarching aim of manipulating BAT function to augment energy expenditure as a countermeasure for obesity and the metabolic abnormalities it incurs. Subsequently, there has been heightened interest in quantifying BAT function and more specifically, determining UCP1-mediated thermogenesis in BAT specimens - including in those obtained from humans. <br />
<br />
In this article, BAT mitochondrial bioenergetics will be described and compared with more conventional mitochondria in other tissues. The biochemical methods typically used to quantify BAT mitochondrial function will also be discussed in terms of their specificity for assaying UCP1 mediated thermogenesis. Finally, recent data concerning BAT UCP1 function in humans will be described and discussed.<br />
|keywords=Brown fat, GDP, UCP1, Mitochondria, Thermogenesis, Review<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US TX Galveston Porter C<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|tissues=Fat<br />
|preparations=Permeabilized tissue, Isolated mitochondria, Intact cells<br />
|enzymes=Uncoupling protein<br />
|couplingstates=LEAK, ROUTINE, OXPHOS, ET<br />
|instruments=Oxygraph-2k<br />
|additional=2019-03,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Ryan_2018_JCI_Insight&diff=184391
Ryan 2018 JCI Insight
2019-08-14T11:56:24Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Ryan TE, Yamaguchi DJ, Schmidt CA, Zeczycki TN, Shaikh SR, Brophy P, Green TD, Tarpey MD, Karnekar R, Goldberg EJ, Sparagna GC, Torres MJ, Annex BH, Neufer PD, Spangenburg EE, McClung JM (2018) Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants. JCI Insight 3:123235.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30385731 PMID: 30385731 Open Access]<br />
|authors=Ryan TE, Yamaguchi DJ, Schmidt CA, Zeczycki TN, Shaikh SR, Brophy P, Green TD, Tarpey MD, Karnekar R, Goldberg EJ, Sparagna GC, Torres MJ, Annex BH, Neufer PD, Spangenburg EE, McClung JM<br />
|year=2018<br />
|journal=JCI Insight<br />
|abstract=The most severe manifestation of peripheral arterial disease (PAD) is critical limb ischemia (CLI). CLI patients suffer high rates of amputation and mortality; accordingly, there remains a clear need both to better understand CLI and to develop more effective treatments. Gastrocnemius muscle was obtained from 32 older (51-84 years) non-PAD controls, 27 claudicating PAD patients (ankle-brachial index [ABI] 0.65 ± 0.21 SD), and 19 CLI patients (ABI 0.35 ± 0.30 SD) for whole transcriptome sequencing and comprehensive mitochondrial phenotyping. Comparable permeabilized myofiber mitochondrial function was paralleled by both similar mitochondrial content and related mRNA expression profiles in non-PAD control and claudicating patient tissues. Tissues from CLI patients, despite being histologically intact and harboring equivalent mitochondrial content, presented a unique bioenergetic signature. This signature was defined by deficits in permeabilized myofiber mitochondrial function and a unique pattern of both nuclear and mitochondrial encoded gene suppression. Moreover, isolated muscle progenitor cells retained both mitochondrial functional deficits and gene suppression observed in the tissue. These findings indicate that muscle tissues from claudicating patients and non-PAD controls were similar in both their bioenergetics profile and mitochondrial phenotypes. In contrast, CLI patient limb skeletal muscles harbor a unique skeletal muscle mitochondriopathy that represents a potentially novel therapeutic site for intervention.<br />
|keywords=Atherosclerosis, Cardiovascular disease, Metabolism, Skeletal muscle, Buffer Z<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US NC Greenville Neufer PD, US CO Aurora Sparagna GC<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|diseases=Cardiovascular<br />
|organism=Human<br />
|tissues=Skeletal muscle<br />
|preparations=Permeabilized tissue<br />
|enzymes=Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N, S, CIV, NS, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2018-11,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=McWilliams_2018_Open_Biol&diff=184386
McWilliams 2018 Open Biol
2019-08-14T11:53:39Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=McWilliams TG, Barini E, Pohjolan-Pirhonen R, Brooks SP, Singh F, Burel S, Balk K, Kumar A, Montava-Garriga L, Prescott AR, Hassoun SM, Mouton-Liger F, Ball G, Hills R, Knebel A, Ulusoy A, Di Monte DA, Tamjar J, Antico O, Fears K, Smith L, Brambilla R, Palin E, Valori M, Eerola-Rautio J, Tienari P, Corti O, Dunnett SB, Ganley IG, Suomalainen A, Muqit MMK (2018) Phosphorylation of Parkin at serine 65 is essential for its activation in vivo. Open Biol 8:180108.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30404819 PMID: 30404819 Open Access]<br />
|authors=McWilliams TG, Barini E, Pohjolan-Pirhonen R, Brooks SP, Singh F, Burel S, Balk K, Kumar A, Montava-Garriga L, Prescott AR, Hassoun SM, Mouton-Liger F, Ball G, Hills R, Knebel A, Ulusoy A, Di Monte DA, Tamjar J, Antico O, Fears K, Smith L, Brambilla R, Palin E, Valori M, Eerola-Rautio J, Tienari P, Corti O, Dunnett SB, Ganley IG, Suomalainen A, Muqit MMK<br />
|year=2018<br />
|journal=Open Biol<br />
|abstract=Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and ''in vitro'' studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation ''in vivo'' in mammals remains unknown. To address this, we generated a ''Parkin'' Ser65Ala (S65A) knock-in mouse model. We observe endogenous Parkin Ser65 phosphorylation and activation in mature primary neurons following mitochondrial depolarization and reveal this is disrupted in ''Parkin'' <sup>S65A/S65A</sup> neurons. Phenotypically, ''Parkin'' <sup>S65A/S65A</sup> mice exhibit selective motor dysfunction in the absence of any overt neurodegeneration or alterations in nigrostriatal mitophagy. The clinical relevance of our findings is substantiated by the discovery of homozygous PARKIN (PARK2) p.S65N mutations in two unrelated patients with PD. Moreover, biochemical and structural analysis demonstrates that the Parkin<sup>S65N/S65N</sup> mutant is pathogenic and cannot be activated by PINK1. Our findings highlight the central role of Parkin Ser65 phosphorylation in health and disease.<br />
|keywords=PINK1, Parkin, Parkinson's disease, Mitochondria, Mitophagy, Neurodegeneration<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, nDNA;cell genetics, Genetic knockout;overexpression<br />
|diseases=Parkinson's<br />
|organism=Mouse<br />
|tissues=Nervous system<br />
|preparations=Homogenate<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=N<br />
|instruments=Oxygraph-2k<br />
|additional=2018-11,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Bombaca_2018_Free_Radic_Biol_Med&diff=184384
Bombaca 2018 Free Radic Biol Med
2019-08-14T11:49:21Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Bombaça ACS, Viana PG, Santos ACC, Silva TL, Rodrigues ABM, Guimarães ACR, Goulart MOF, Da Silva Júnior EN, Menna-Barreto RFS (2018) Mitochondrial disfunction and ROS production are essential for anti-Trypanosoma cruzi activity of β-lapachone-derived naphthoimidazoles. Free Radic Biol Med 130:408-18.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30445126 PMID: 30445126 Open Access]<br />
|authors=Bombaca ACS, Viana PG, Santos ACC, Silva TL, Rodrigues ABM, Guimaraes ACR, Goulart MOF, Da Silva Junior EN, Menna-Barreto RFS<br />
|year=2018<br />
|journal=Free Radic Biol Med<br />
|abstract=Chagas disease is caused by the hemoflagellate protozoa ''Trypanosoma cruzi'' and is one of the most important neglected tropical diseases, especially in Latin American countries, where there is an association between low-income populations and mortality. The nitroderivatives used in current chemotherapy are far from ideal and present severe limitations, justifying the continuous search for alternative drugs. Since the1990s, our group has been investigating the trypanocidal activity of natural naphthoquinones and their derivatives, and three naphthoimidazoles (N1, N2 and N3) derived from β-lapachone were found to be most effective ''in vitro''. Analysis of their mechanism of action via cellular, molecular and proteomic approaches indicates that the parasite mitochondrion contains one of the primary targets of these compounds, trypanothione synthetase (involved in trypanothione production), which is overexpressed after treatment with these compounds. Here, we further evaluated the participation of the mitochondria and reactive oxygen species (ROS) in the anti-''T. cruzi'' action of naphthoimidazoles. Preincubation of epimastigotes and trypomastigotes with antioxidants (α-tocopherol and urate) strongly protected the parasites from the trypanocidal effect of naphthoimidazoles, decreasing the ROS levels produced and reverting the mitochondrial swelling phenotype. The addition of pro-oxidants (menadione and H<sub>2</sub>O<sub>2</sub>) before the treatment induced an increase in parasite lysis. Despite the O<sub>2</sub> uptake and mitochondrial complex activity being strongly reduced by N1, N2 and N3, urate partially restored the mitochondrial metabolism only in N1-treated parasites. In parallel, MitoTEMPO, a mitochondrial-targeted antioxidant, protected the functionality of the mitochondria in N2- and N3-treated parasites. In addition, the trypanothione reductase activity was remarkably increased after treatment with N1 and N3, and molecular docking demonstrated that these two compounds were positioned in pockets of this enzyme. Based on our findings, the direct impairment of the mitochondrial electron transport chain by N2 and N3 led to an oxidative misbalance, which exacerbated ROS generation and led to parasite death. Although other mechanisms cannot be discounted, mainly in N1-treated parasites, further investigations are required.<br />
|keywords=Chagas disease, Trypanosoma cruzi, Antioxidant defenses, Chemotherapy, Mitochondria, Naphthoimidazoles, Reactive oxygen species<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, Pharmacology;toxicology<br />
|diseases=Infectious<br />
|organism=Protists<br />
|preparations=Intact organism<br />
|enzymes=Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase<br />
|couplingstates=ROUTINE<br />
|pathways=ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2018-11,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Giordano_2018_Am_J_Respir_Cell_Mol_Biol&diff=184378
Giordano 2018 Am J Respir Cell Mol Biol
2019-08-14T11:21:07Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Giordano L, Farnham A, Dhandapani PK, Salminen L, Bhaskaran J, Voswinckel R, Rauschkolb P, Scheibe S, Sommer N, Beisswenger C, Weissmann N, Braun T, Jacobs HT, Bals R, Herr C, Szibor M (2018) Alternative oxidase attenuates cigarette smoke-induced lung dysfunction and tissue damage. Am J Respir Cell Mol Biol 60:515-22.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30339461 PMID: 30339461]<br />
|authors=Giordano L, Farnham A, Dhandapani PK, Salminen L, Bhaskaran J, Voswinckel R, Rauschkolb P, Scheibe S, Sommer N, Beisswenger C, Weissmann N, Braun T, Jacobs HT, Bals R, Herr C, Szibor M<br />
|year=2018<br />
|journal=Am J Respir Cell Mol Biol<br />
|abstract=Cigarette-smoke (CS) exposure is the predominant risk factor for the development of chronic obstructive pulmonary disease (COPD) and the third leading cause of death worldwide. We aimed to elucidate if mitochondrial respiratory inhibition and oxidative stress are triggers in its etiology. In different models of CS exposure, we investigated the effect on lung remodeling and cell signaling of restoring mitochondrial respiratory electron flow, using the alternative oxidase (AOX), which by-passes the cytochrome segment of the respiratory chain. AOX attenuated CS-induced lung tissue destruction and loss of function in mice exposed chronically to CS (for 9 months). It preserved cell viability of isolated mouse embryonic fibroblasts (MEFs) treated with cigarette smoke condensate (CSC), limited the induction of apoptosis and decreased the production of reactive oxygen species (ROS). In contrast, the early-phase inflammatory response induced by acute CS exposure of mouse lung, i.e. infiltration by macrophages and neutrophils and adverse signaling, was unaffected. The use of AOX allowed novel pathomechanistic insights into CS-induced cell damage, mitochondrial ROS production and lung remodeling. Our findings implicate mitochondrial respiratory inhibition as a key pathogenic mechanism of CS toxicity in the lung. We propose AOX as a novel tool to study CS-related lung remodeling and potentially counteract CS-induced ROS production and cell damage.<br />
|keywords=Cigarette smoke, COPD, Mitochondria, Alternative oxidase<br />
|editor=[[Plangger M]],<br />
|mipnetlab=FI Helsinki Jacobs HT, DE Giessen Weissmann N<br />
}}<br />
{{Labeling<br />
|area=Respiration, Pharmacology;toxicology<br />
|diseases=COPD<br />
|injuries=Oxidative stress;RONS<br />
|organism=Mouse<br />
|tissues=Fibroblast<br />
|preparations=Permeabilized cells<br />
|couplingstates=OXPHOS<br />
|pathways=N, S, CIV, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Castellano-Gonzalez_2019_Neurotox_Res&diff=184377
Castellano-Gonzalez 2019 Neurotox Res
2019-08-14T11:15:43Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Castellano-Gonzalez G, Jacobs KR, Don E, Cole NJ, Adams S, Lim CK, Lovejoy DB, Guillemin GJ (2019) Kynurenine 3-monooxygenase activity in human primary neurons and effect on cellular bioenergetics identifies new neurotoxic mechanisms. Neurotox Res 35:530-41.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30666558 PMID: 30666558]<br />
|authors=Castellano-Gonzalez G, Jacobs KR, Don E, Cole NJ, Adams S*, Lim CK, Lovejoy DB, Guillemin GJ<br />
|year=2019<br />
|journal=Neurotox Res<br />
|abstract=Upregulation of the kynurenine pathway (KP) of tryptophan metabolism is commonly observed in neurodegenerative disease. When activated, L-kynurenine (KYN) increases in the periphery and central nervous system where it is further metabolised to other neuroactive metabolites including 3-hydroxykynurenine (3-HK), kynurenic acid (KYNA) and quinolinic acid (QUIN). Particularly biologically relevant metabolites are 3-HK and QUIN, formed downstream of the enzyme kynurenine 3-monooxygenase (KMO) which plays a pivotal role in maintaining KP homeostasis. Indeed, excessive production of 3-HK and QUIN has been described in neurodegenerative disease including Alzheimer's disease and Huntington's disease. In this study, we characterise KMO activity in human primary neurons and identified new mechanisms by which KMO activation mediates neurotoxicity. We show that while transient activation of the KP promotes synthesis of the essential co-enzyme nicotinamide adenine dinucleotide (NAD<sup>+</sup>), allowing cells to meet short-term increased energy demands, chronic KMO activation induces production of reactive oxygen species (ROS), mitochondrial damage and decreases spare-respiratory capacity (SRC). We further found that these events generate a vicious-cycle, as mitochondrial dysfunction further shunts the KP towards the KMO branch of the KP to presumably enhance QUIN production. These mechanisms may be especially relevant in neurodegenerative disease as neurons are highly sensitive to oxidative stress and mitochondrial impairment.<br />
|keywords=Kynurenine 3-monooxygenase, Kynurenine pathway, Mitochondrial dysfunction, Oxidative stress<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, Pharmacology;toxicology<br />
|diseases=Neurodegenerative<br />
|injuries=Oxidative stress;RONS<br />
|organism=Human<br />
|tissues=HEK<br />
|preparations=Intact cells<br />
|couplingstates=LEAK, ROUTINE, ET<br />
|pathways=ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Vicentini_2019_Plant_Physiol_Biochem&diff=184375
Vicentini 2019 Plant Physiol Biochem
2019-08-14T10:34:57Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Vicentini TM, Cavalheiro AH, Dechandt CRP, Alberici LC, Vargas-Rechia CG (2019) Aluminum directly inhibits alternative oxidase pathway and changes metabolic and redox parameters on ''Jatropha curcas'' cell culture. Plant Physiol Biochem 136:92-97.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30660100 PMID: 30660100]<br />
|authors=Vicentini TM, Cavalheiro AH, Dechandt CRP, Alberici LC, Vargas-Rechia CG<br />
|year=2019<br />
|journal=Plant Physiol Biochem<br />
|abstract=Aluminum (Al) toxicity has been recognized to be a main limiting factor of crop productivity in acid soil. Al interacts with cell walls disrupting the functions of the plasma membrane and is associated with oxidative damage and mitochondrial dysfunction. ''Jatropha curcas'' L. (''J. curcas'') is a drought resistant plant, widely distributed around the world, with great economic and medicinal importance. Here we investigated the effects of Al on ''J. curcas'' mitochondrial function and cell viability, analyzing mitochondrial respiration, phenolic compounds, reducing sugars and cell viability in cultured ''J. curcas'' cells. The results showed that at 70 μM, Al limited mitochondrial respiration by inhibiting the alternative oxidase (AOX) pathway in the respiratory chain. An increased concentration of reducing sugars and reduced concentration of intracellular phenolic compounds was observed during respiratory inhibition. After inhibition, a time-dependent upregulation of AOX mRNA was observed followed by restoration of respiratory activity and reducing sugar concentrations. Cultured ''J. curcas'' cells were very resistant to Al-induced cell death. In addition, at 70 μM, Al also appeared as an inhibitor of cell wall invertase. In conclusion, Al tolerance in cultured ''J. curcas'' cells involves a inhibition of mitochondrial AOX pathway, which seems to start an oxidative burst to induce AOX upregulation, which in turn restores consumption of O<sub>2</sub> and substrates. These data provide new insight into the signaling cascades that modulate the Al tolerance mechanism.<br />
<br />
<small>Copyright © 2019 Elsevier Masson SAS. All rights reserved.</small><br />
|keywords=Alternative oxidase, Invertase activity, Jatropha curcas cell culture, Mitochondrial respiration, Phenolic compounds, Reducing sugars<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, Pharmacology;toxicology<br />
|organism=Plants<br />
|preparations=Intact cells<br />
|couplingstates=ROUTINE<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Mousovich-Neto_2019_Exp_Physiol&diff=184374
Mousovich-Neto 2019 Exp Physiol
2019-08-14T10:30:03Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Mousovich-Neto F, Matos MS, Costa ACR, de Melo Reis RA, Atella GC, Miranda-Alves L, Carvalho DP, Ketzer LA, Corrêa da Costa VM (2019) Brown adipose tissue remodeling induced by corticosterone in Wistar male rats. Exp Physiol 104:514-28.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30653762 PMID: 30653762]<br />
|authors=Mousovich-Neto F, Matos MS, Costa ACR, de Melo Reis RA, Atella GC, Miranda-Alves L, Carvalho DP, Ketzer LA, Correa da Costa VM<br />
|year=2019<br />
|journal=Exp Physiol<br />
|abstract=In mammals, brown adipose tissue (BAT) is centrally involved in energy metabolism. To test the hypothesis that glucocorticoids excess disrupts BAT phenotype and function, male Wistar rats were treated with corticosterone in drinking water for 21 days. To confirm induction of glucocorticoid excess and metabolic disturbances, adrenals weight, corticotrophin releasing hormone mRNA levels, corticosterone serum levels, glucose tolerance test and serum triacylglycerol analyses were performed. Adipose tissue deposits were excised, weighed and evaluated by a set of biochemical, histological and molecular procedures, such as: thin-layer chromatography, histochemistry, immunohistochemistry, quantitative real-time polymerase chain reaction, high-resolution oxygraphy, ATP synthesis and enzymatic activity measurements. The approach was successful in induction of glucocorticoid excess and metabolic disturbances. Lower body weight and increased adiposity were observed in corticosterone-treated rats. Interscapular brown adipose tissue (iBAT) showed higher sensitivity to glucocorticoids than other fat deposits. The treatment induced lipid accumulation, unilocular rearrangement, increased collagen content and decreased innervation in iBAT. Furthermore, expression of ''Prdm16'' (P < 0.05), ''Ucp1'' (P < 0.05) and ''Slc7a10'' (P < 0.05) decreased, while expression of ''Fasn'' (P < 0.05) and ''Lep'' (P < 0.05) mRNA increased in brown adipose tissue. Also, the levels of UCP1 diminished (P < 0.001, 2.5-fold). Finally, lower oxygen consumption (P < 0.05), ATP synthesis (P < 0.05) and mitochondrial content (P < 0.05) were observed in iBAT of GCs-treated rats. Glucocorticoid excess induced an extensive remodeling of interscapular brown adipose tissue, resulting in a white-like phenotype in association with metabolic disturbances. This article is protected by copyright. All rights reserved.<br />
<br />
<small>This article is protected by copyright. All rights reserved.</small><br />
|keywords=Brown adipose tissue, Glucocorticoids, Metabolic disturbances<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, nDNA;cell genetics, Exercise physiology;nutrition;life style, Pharmacology;toxicology<br />
|organism=Rat<br />
|tissues=Fat<br />
|preparations=Isolated mitochondria<br />
|topics=ATP production<br />
|couplingstates=OXPHOS<br />
|pathways=NS<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Wang_2019_Free_Radic_Biol_Med&diff=184373
Wang 2019 Free Radic Biol Med
2019-08-14T10:04:16Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Wang SQ, Yang XY, Cui SX, Gao ZH, Qu XJ (2019) Heterozygous knockout insulin-like growth factor-1 receptor (IGF-1R) regulates mitochondrial functions and prevents colitis and colorectal cancer. Free Radic Biol Med 134:87-98.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30611867 PMID: 30611867]<br />
|authors=Wang SQ, Yang XY, Cui SX, Gao ZH, Qu XJ<br />
|year=2019<br />
|journal=Free Radic Biol Med<br />
|abstract=Although insulin-like growth factor-1 receptor (IGF-1R) has been accepted as a major determinant of cancers, its biological roles and corresponding mechanisms in tumorigenesis have remained elusive. Herein, we demonstrate that IGF-1R plays pivotal roles in the regulation of mitochondrial respiratory chain and functions during colitis and tumorigenesis. Heterozygous knockout IGF-1R attenuated azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis and colitis associated cancer (CAC) in Igf1r<sup>+/-</sup> mice. Heterozygous knockout IGF-1R confers resistance to oxidative stress-induced damage on colorectal epithelial cells by protecting mitochondrial dynamics and structures. IGF-1R low expression improves the biological function of mitochondrial fusion under oxidative stress. Mechanically, an increase in respiratory coupling index (RCI) and oxidative phosphorylation index (ADP/O) was seen in colorectal epithelial cells of Igf1r<sup>+/-</sup> mice. Seahorse XF<sup>e</sup>-24 analyzer analysis of mitochondrial bioenergetics demonstrated an increase in oxygen consumption rate (OCR) and a decrease of extracellular acidification rate (ECAR) in Igf1r<sup>+/-</sup> cells. Further analysis suggests the protection mechanisms of Igf1r<sup>+/-</sup> cells from oxidative stress through the activation of the mitochondrial respiratory chain and LKB1/AMPK pathways. These results highlight the biological roles of IGF-1R at the nexus between oxidative damage and mitochondrial function and a connection between colitis and colorectal cancer.<br />
<br />
<small>Copyright © 2019 Elsevier Inc. All rights reserved.</small><br />
|keywords=Colitis-associated cancer, IGF-1R, LKB1/AMPK pathways, Mitochondrial functions, Oxidative stress, Ulcerative colitis<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, Genetic knockout;overexpression<br />
|diseases=Cancer<br />
|injuries=Oxidative stress;RONS<br />
|organism=Mouse<br />
|tissues=Heart, Liver, Endothelial;epithelial;mesothelial cell<br />
|preparations=Isolated mitochondria<br />
|couplingstates=LEAK, OXPHOS<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Malyala_2019_PLoS_Comput_Biol&diff=184372
Malyala 2019 PLoS Comput Biol
2019-08-14T10:00:36Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Malyala S, Zhang Y, Strubbe JO, Bazil JN (2019) Calcium phosphate precipitation inhibits mitochondrial energy metabolism. PLoS Comput Biol 15:e1006719.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30615608 PMID: 30615608 Open Access]<br />
|authors=Malyala S, Zhang Yizhu, Strubbe JO, Bazil JN<br />
|year=2019<br />
|journal=PLoS Comput Biol<br />
|abstract=Early studies have shown that moderate levels of calcium overload can cause lower oxidative phosphorylation rates. However, the mechanistic interpretations of these findings were inadequate. And while the effect of excessive calcium overload on mitochondrial function is well appreciated, there has been little to no reports on the consequences of low to moderate calcium overload. To resolve this inadequacy, mitochondrial function from guinea pig hearts was quantified using several well-established methods including high-resolution respirometry and spectrofluorimetry and analyzed using mathematical modeling. We measured key mitochondrial variables such as respiration, mitochondrial membrane potential, buffer calcium, and substrate effects for a range of mitochondrial calcium loads from near zero to levels approaching mitochondrial permeability transition. In addition, we developed a computer model closely mimicking the experimental conditions and used this model to design experiments capable of eliminating many hypotheses generated from the data analysis. We subsequently performed those experiments and determined why mitochondrial ADP-stimulated respiration is significantly lowered during calcium overload. We found that when calcium phosphate levels, not matrix free calcium, reached sufficient levels, complex I activity is inhibited, and the rate of ATP synthesis is reduced. Our findings suggest that calcium phosphate granules form physical barriers that isolate complex I from NADH, disrupt complex I activity, or destabilize cristae and inhibit NADH-dependent respiration.<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US MI East Lansing Bazil J<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|organism=Guinea pig<br />
|tissues=Heart<br />
|preparations=Isolated mitochondria<br />
|topics=Calcium, mt-Membrane potential<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N, S<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Rawat_2019_J_Mol_Biol&diff=184371
Rawat 2019 J Mol Biol
2019-08-14T09:11:21Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Rawat S, Anusha V, Jha M, Sreedurgalakshmi K, Raychaudhuri S (2019) Aggregation of respiratory complex subunits marks the onset of proteotoxicity in proteasome inhibited cells. J Mol Biol 431:996-1015.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30682348 PMID: 30682348 Open Access]<br />
|authors=Rawat S, Anusha V, Jha M, Sreedurgalakshmi K, Raychaudhuri S<br />
|year=2019<br />
|journal=J Mol Biol<br />
|abstract=Proteostasis is maintained by optimal expression, folding, transport, and clearance of proteins. Deregulation of any of these processes triggers protein aggregation and is implicated in many age-related pathologies. In this study, using quantitative proteomics and microscopy, we show that aggregation of many nuclear-encoded mitochondrial proteins is an early protein-destabilization event during short-term proteasome inhibition. Among these, Respiratory Chain Complex (RCC) subunits represent a group of functionally related proteins consistently forming aggregates under multiple proteostasis-stresses with varying aggregation-propensities. Sequence analysis reveals that several RCC subunits, irrespective of the cleavable mitochondrial targeting sequence (MTS), contain low complexity regions (LCR) at the N-terminus. Using different chimeric and mutant constructs, we show that these low complexity regions partially contribute to the intrinsic instability of multiple RCC subunits. Taken together, we propose that physicochemically driven aggregation of unassembled RCC subunits destabilizes their functional assembly inside mitochondria. This eventually deregulates the biogenesis of respiratory complexes and marks the onset of mitochondrial dysfunction.<br />
<br />
<small>Copyright © 2019. Published by Elsevier Ltd.</small><br />
|keywords=Low complexity region, Mitochondria, Mitochondrial respiratory chain complex, Protein aggregation, Protein misfolding, Protein turnover, Proteomics, Proteostasis, Neuro2a mouse neuroblastoma cells<br />
|editor=[[Plangger M]],<br />
|mipnetlab=IN Hyderabad Thangaraj K<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|organism=Mouse<br />
|tissues=Nervous system, Other cell lines<br />
|preparations=Permeabilized cells<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N, S, CIV, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Paumelle_2019_J_Hepatol&diff=184368
Paumelle 2019 J Hepatol
2019-08-14T09:03:51Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Paumelle R, Haas J, Hennuyer N, Bauge E, Deleye Y, Mesotten D, Langouche L, Vanhoutte J, Cudejko C, Wouters K, Hannou SA, Legry V, Lancel S, Lalloyer F, Polizzi A, Smati S, Gourdy P, Vallez E, Bouchaert E, Derudas B, Dehondt H, Gheeraert C, Fleury S, Tailleux A, Montagner A, Wahli W, Van Den Berghe G, Guillou H, Dombrowicz D, Staels B (2019) Hepatic PPARα is critical in the metabolic adaptation to sepsis. J Hepatol 70:963-73.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30677458 PMID: 30677458]<br />
|authors=Paumelle R, Haas J, Hennuyer N, Bauge E, Deleye Y, Mesotten D, Langouche L, Vanhoutte J, Cudejko C, Wouters K, Hannou SA, Legry V, Lancel S, Lalloyer F, Polizzi A, Smati S, Gourdy P, Vallez E, Bouchaert E, Derudas B, Dehondt H, Gheeraert C, Fleury S, Tailleux A, Montagner A, Wahli W, Van Den Berghe G, Guillou H, Dombrowicz D, Staels B<br />
|year=2019<br />
|journal=J Hepatol<br />
|abstract=Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)α, which controls both lipid metabolism and inflammation. However, the role of hepatic PPARα in the response to sepsis is unknown.<br />
<br />
Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Pparα-deficiency and their controls. The systemic and hepatic metabolic response was analysed using biochemical, transcriptomic and functional assays. PPARα expression was analysed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters RESULTS: Both whole body and non-hematopoietic Pparα-deficiency in mice decreased survival upon bacterial infection. Livers of septic Pparα-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPARα impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPARA expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers.<br />
<br />
Metabolic control by PPARα in hepatocytes plays a key role in the host defense to infection. Lay summary: As the main cause of death of critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have been mostly overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPARα in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes.<br />
<br />
<small>Copyright © 2019. Published by Elsevier B.V.</small><br />
|keywords=Hepatocytes, Inflammation, Metabolism, Nuclear receptors, Sepsis<br />
|editor=[[Plangger M]],<br />
|mipnetlab=FR Lille Duez H<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|diseases=Infectious, Sepsis<br />
|organism=Human<br />
|tissues=Liver<br />
|preparations=Homogenate<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=F, N<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Larsen_2019_Appl_Physiol_Nutr_Metab&diff=184365
Larsen 2019 Appl Physiol Nutr Metab
2019-08-14T08:15:39Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Larsen S, Dandanell S, Kristensen KB, Jørgensen SD, Dela F, Helge JW (2019) Influence of exercise amount and intensity on long-term weight loss maintenance and skeletal muscle mitochondrial ROS production in humans. Appl Physiol Nutr Metab [Epub ahead of print].<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30664360 PMID: 30664360]<br />
|authors=Larsen S, Dandanell S, Kristensen KB, Joergensen SD, Dela F, Helge JW<br />
|year=2019<br />
|journal=Appl Physiol Nutr Metab<br />
|abstract=Sustaining a weight loss after a lifestyle intervention is challenging. The objective of the present study was to investigate if mitochondrial function is associated to the ability to maintain a weight loss. 68 former participants in an 11-12-week lifestyle intervention were recruited into two groups; weight loss maintenance (WLM; BMI 32±1 kg/m<sup>2</sup>) and weight regain (WR; BMI 43±2 kg/m<sup>2</sup>) based on weight loss measured at a follow-up visit (WLM: 4.8±0.4; WR: 7.6±0.8 years after lifestyle intervention). Maximal oxygen consumption rate (VO<sub>2max</sub>), physical activity level, blood and muscle samples were obtained at the follow up experiment. Mitochondrial respiratory capacity and reactive oxygen species (ROS) production were measured. Fasting blood samples were used to calculate glucose homeostasis index. WR had an impaired glucose homeostasis a decreased VO<sub>2max</sub> and physical activity level compared with WLM. The decreased physical activity in WR was due to a lower activity level at vigorous and moderate intensities. Mitochondrial respiratory capacity and citrate synthase (CS) activity was higher in WLM, but intrinsic mitochondrial respiratory capacity (mitochondrial respiratory capacity corrected for mitochondrial content (CS activity)) was similar. ROS production was higher in WR compared with WLM, this was accompanied by a decreased content of antioxidant proteins in WR. Skeletal muscle intrinsic mitochondrial respiratory capacity is not associated with the ability to maintain a long-term weight loss. WLM had a higher VO<sub>2max</sub>, physical activity level, mitochondrial respiratory capacity and CS activity compared with WR. The reduced glucose tolerance was concurrent with increased ROS production per mitochondria in WR, and could also be associated with the lower physical activity level in this group.<br />
|keywords=Glucose tolerance, Mitochondrial content, Mitochondrial function, Reactive oxygen species production, Skeletal muscle, Weight loss<br />
|editor=[[Plangger M]],<br />
|mipnetlab=DK Copenhagen Dela F, DK Copenhagen Larsen S<br />
}}<br />
{{Labeling<br />
|area=Respiration, Exercise physiology;nutrition;life style<br />
|organism=Human<br />
|tissues=Skeletal muscle<br />
|preparations=Permeabilized tissue<br />
|enzymes=Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase<br />
|topics=ADP<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=N, NS<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Zhang_2018_Cardiovasc_Diabetol&diff=184364
Zhang 2018 Cardiovasc Diabetol
2019-08-14T08:13:41Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Zhang X, Zhang Z, Yang Y, Suo Y, Liu R, Qiu J, Zhao Y, Jiang N, Liu C, Tse G, Li G, Liu T (2018) Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits. Cardiovasc Diabetol 17:160.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30591063 PMID: 30591063 Open Access]<br />
|authors=Zhang X*, Zhang Z, Yang Y*, Suo Y, Liu R, Qiu J, Zhao Y, Jiang N, Liu C*, Tse G, Li G, Liu T<br />
|year=2018<br />
|journal=Cardiovasc Diabetol<br />
|abstract=There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits.<br />
<br />
A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed ''in vivo''. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-β1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting.<br />
<br />
DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e' ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (- dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway.<br />
<br />
The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.<br />
|keywords=Diabetes mellitus, Diabetic cardiomyopathy, Dipeptidyl peptidase-4 inhibitors, Mitochondrial biogenesis, Mitochondrial function<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, mt-Biogenesis;mt-density, Pharmacology;toxicology<br />
|diseases=Cardiovascular, Diabetes<br />
|injuries=Oxidative stress;RONS<br />
|organism=Rabbit<br />
|tissues=Heart<br />
|preparations=Isolated mitochondria<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Gonzalez-Mariscal_2019_FASEB_J&diff=184363
Gonzalez-Mariscal 2019 FASEB J
2019-08-14T08:06:20Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=González-Mariscal I, Montoro RA, O'Connell JF, Kim Y, Gonzalez-Freire M, Liu QR, Alfaras I, Carlson OD, Lehrmann E, Zhang Y, Becker KG, Hardivillé S, Ghosh P, Egan JM (2019) Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism. FASEB J 33:5850-63.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30726112 PMID: 30726112]<br />
|authors=Gonzalez-Mariscal I, Montoro RA, O'Connell JF, Kim Y, Gonzalez-Freire M, Liu QR, Alfaras I, Carlson OD, Lehrmann E, Zhang Y*, Becker KG, Hardiville S, Ghosh P, Egan JM<br />
|year=2019<br />
|journal=FASEB J<br />
|abstract=Sarcopenic obesity, the combination of skeletal muscle mass and function loss with an increase in body fat, is associated with physical limitations, cardiovascular diseases, metabolic stress, and increased risk of mortality. Cannabinoid receptor type 1 (CB1R) plays a critical role in the regulation of whole-body energy metabolism because of its involvement in controlling appetite, fuel distribution, and utilization. Inhibition of CB1R improves insulin secretion and insulin sensitivity in pancreatic β-cells and hepatocytes. We have now developed a skeletal muscle-specific CB1R-knockout (Skm-CB1R<sup>-/-</sup>) mouse to study the specific role of CB1R in muscle. Muscle-CB1R ablation prevented diet-induced and age-induced insulin resistance by increasing IR signaling. Moreover, muscle-CB1R ablation enhanced AKT signaling, reducing myostatin expression and increasing IL-6 secretion. Subsequently, muscle-CB1R ablation increased myogenesis through its action on MAPK-mediated myogenic gene expression. Consequently, Skm-CB1R<sup>-/-</sup> mice had increased muscle mass and whole-body lean/fat ratio in obesity and aging. Muscle-CB1R ablation improved mitochondrial performance, leading to increased whole-body muscle energy expenditure and improved physical endurance, with no change in body weight. These results collectively show that CB1R in muscle is sufficient to regulate whole-body metabolism and physical performance and is a novel target for the treatment of sarcopenic obesity.<br />
|keywords=CB1R, Insulin sensitivity, Myokines, Skeletal muscle<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US MD Baltimore Ferrucci L<br />
}}<br />
{{Labeling<br />
|area=Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style<br />
|diseases=Obesity<br />
|organism=Mouse<br />
|tissues=Skeletal muscle<br />
|preparations=Permeabilized tissue<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=N, S, NS, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-02,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Hughes_2019_J_Physiol&diff=184362
Hughes 2019 J Physiol
2019-08-14T07:51:58Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Hughes MC, Ramos SV, Turnbull PC, Edgett BA, Huber JS, Polidovitch N, Schlattner U, Backx PH, Simpson JA, Perry CGR (2019) Impairments in left ventricular mitochondrial bioenergetics precede overt cardiac dysfunction and remodelling in Duchenne muscular dystrophy. J Physiol [Epub ahead of print].<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30674086 PMID: 30674086]<br />
|authors=Hughes MC, Ramos SV, Turnbull PC, Edgett BA, Huber JS, Polidovitch N, Schlattner U, Backx PH, Simpson JA, Perry CGR<br />
|year=2019<br />
|journal=J Physiol<br />
|abstract=In Duchenne muscular dystrophy (DMD), mitochondrial dysfunction is predicted as a response to numerous cellular stressors yet the degree and contribution of mitochondria to the onset of cardiomyopathy remains unknown. To resolve this uncertainty, we designed ''in vitro'' assessments of mitochondrial bioenergetics to model mitochondrial control parameters that influence cardiac function. Both left ventricular mitochondrial responsiveness to the central bioenergetic controller ADP as well as the ability of creatine to facilitate mitochondrial-cytoplasmic phosphate shuttling were assessed. These measurements were performed in D2.B10-DMD<sup>mdx</sup>/2J mice - a model that demonstrates skeletal muscle atrophy and weakness due to limited regenerative capacities and cardiomyopathy more akin to people with DMD than classic models. At 4 weeks of age, there was no evidence of cardiac remodelling or cardiac dysfunction despite impairments in ADP-stimulated respiration and ADP- attenuation of H<sub>2</sub>O<sub>2</sub> emission. These impairments were seen at both sub-maximal and maximal ADP concentrations despite no reductions in mitochondrial content markers. The ability of creatine to enhance ADP's control of mitochondrial bioenergetics was also impaired, suggesting an impairment in mitochondrial creatine kinase-dependent phosphate shuttling. Susceptibly to permeability transition pore opening and the subsequent activation of cell death pathways remained unchanged. Mitochondrial H<sub>2</sub>O<sub>2</sub> emission was elevated despite no change in markers of irreversible oxidative damage, suggesting alternative redox signalling mechanisms should be explored. These findings demonstrate that selective mitochondrial dysfunction precedes the onset of overt cardiomyopathy in D2.mdx mice, suggesting that improving mitochondrial bioenergetics by restoring ADP, creatine-dependent phosphate shuttling and Complex I should be considered for treating DMD patients.<br />
<br />
<small>This article is protected by copyright. All rights reserved.</small><br />
|keywords=Duchenne muscular dystrophy, Cardiomyopathy, Mitochondria, Reactive oxygen species, Respiration<br />
|editor=[[Plangger M]],<br />
|mipnetlab=CA Toronto Perry CG, FR Grenoble Schlattner U<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|diseases=Myopathy<br />
|organism=Mouse<br />
|tissues=Heart<br />
|preparations=Permeabilized tissue<br />
|topics=Calcium<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N, NS<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Zverova_2019_Neuropsychiatr_Dis_Treat&diff=184361
Zverova 2019 Neuropsychiatr Dis Treat
2019-08-14T07:49:00Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Zvěřová M, Hroudová J, Fišar Z, Hansíková H, Kališová L, Kitzlerová E, Lambertová A, Raboch J (2019) Disturbances of mitochondrial parameters to distinguish patients with depressive episode of bipolar disorder and major depressive disorder. Neuropsychiatr Dis Treat 15:233-40.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30679909 PMID: 30679909 Open Access]<br />
|authors=Zverova M, Hroudova J, Fisar Z, Hansikova H, Kalisova L, Kitzlerova E, Lambertova A, Raboch J<br />
|year=2019<br />
|journal=Neuropsychiatr Dis Treat<br />
|abstract=Mitochondrial dysfunctions are implicated in the pathophysiology of mood disorders. We measured and examined the following selected mitochondrial parameters: citrate synthase (CS) activity, electron transport system (ETS) complex (complexes I, II, and IV) activities, and mitochondrial respiration in blood platelets.<br />
<br />
The analyses were performed for 24 patients suffering from a depressive episode of bipolar affective disorder (BD), compared to 68 patients with MDD and 104 healthy controls. BD and unipolar depression were clinically evaluated using well-established diagnostic scales and questionnaires.<br />
<br />
The CS, complex II, and complex IV activities were decreased in the depressive episode of BD patients; complex I and complex I/CS ratio were significantly increased compared to healthy controls. We observed significantly decreased complex II and CS activities in patients suffering from MDD compared to controls. Decreased respiration after complex I inhibition and increased residual respiration were found in depressive BD patients compared to controls. Physiological respiration and capacity of the ETS were decreased, and respiration after complex I inhibition was increased in MDD patients, compared to controls. Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities.<br />
<br />
We can conclude that complex I and its abnormal activity contribute to the defects in cellular energy metabolism during a depressive episode of BD. The observed parameters could be used in a panel of biomarkers that could selectively distinguish BD depression from MDD and can be easily examined from blood elements.<br />
|keywords=Affective disorder, Biomarker, Mitochondrial enzyme, Oxidative phosphorylation, Platelet<br />
|editor=[[Plangger M]],<br />
|mipnetlab=CZ Prague Fisar Z, CZ Prague Zeman J<br />
}}<br />
{{Labeling<br />
|area=Respiration, Patients<br />
|diseases=Other<br />
|organism=Human<br />
|tissues=Platelet<br />
|preparations=Intact cells<br />
|enzymes=Complex I, Complex II;succinate dehydrogenase, Complex IV;cytochrome c oxidase<br />
|couplingstates=LEAK, ROUTINE, ET<br />
|pathways=ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Richter_2019_Life_Sci_Alliance&diff=184360
Richter 2019 Life Sci Alliance
2019-08-14T07:46:59Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Richter U, Ng KY, Suomi F, Marttinen P, Turunen T, Jackson C, Suomalainen A, Vihinen H, Jokitalo E, Nyman TA, Isokallio MA, Stewart JB, Mancini C, Brusco A, Seneca S, Lombès A, Taylor RW, Battersby BJ (2019) Mitochondrial stress response triggered by defects in protein synthesis quality control. Life Sci Alliance 2:e201800219.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30683687 PMID: 30683687 Open Access]<br />
|authors=Richter U, Ng KY, Suomi F, Marttinen P, Turunen T, Jackson C, Suomalainen A, Vihinen H, Jokitalo E, Nyman TA, Isokallio MA, Stewart JB, Mancini C, Brusco A, Seneca S, Lombes A, Taylor RW, Battersby BJ<br />
|year=2019<br />
|journal=Life Sci Alliance<br />
|abstract=Mitochondria have a compartmentalized gene expression system dedicated to the synthesis of membrane proteins essential for oxidative phosphorylation. Responsive quality control mechanisms are needed to ensure that aberrant protein synthesis does not disrupt mitochondrial function. Pathogenic mutations that impede the function of the mitochondrial matrix quality control protease complex composed of AFG3L2 and paraplegin cause a multifaceted clinical syndrome. At the cell and molecular level, defects to this quality control complex are defined by impairment to mitochondrial form and function. Here, we establish the etiology of these phenotypes. We show how disruptions to the quality control of mitochondrial protein synthesis trigger a sequential stress response characterized first by OMA1 activation followed by loss of mitochondrial ribosomes and by remodelling of mitochondrial inner membrane ultrastructure. Inhibiting mitochondrial protein synthesis with chloramphenicol completely blocks this stress response. Together, our data establish a mechanism linking major cell biological phenotypes of AFG3L2 pathogenesis and show how modulation of mitochondrial protein synthesis can exert a beneficial effect on organelle homeostasis.<br />
<br />
<small>© 2019 Richter et al.</small><br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, mt-Biogenesis;mt-density, mtDNA;mt-genetics, Genetic knockout;overexpression<br />
|organism=Human<br />
|tissues=Fibroblast<br />
|preparations=Permeabilized cells<br />
|couplingstates=OXPHOS, ET<br />
|pathways=N, CIV, NS<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Veyrat-Durebex_2019_Mol_Neurobiol&diff=184359
Veyrat-Durebex 2019 Mol Neurobiol
2019-08-14T07:43:26Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Veyrat-Durebex C, Bris C, Codron P, Bocca C, Chupin S, Corcia P, Vourc'h P, Hergesheimer R, Cassereau J, Funalot B, Andres CR, Lenaers G, Couratier P, Reynier P, Blasco H (2019) Metabo-lipidomics of fibroblasts and mitochondrial-endoplasmic reticulum extracts from ALS patients shows alterations in purine, pyrimidine, energetic, and phospholipid metabolisms. Mol Neurobiol [Epub ahead of print].<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30680691 PMID: 30680691]<br />
|authors=Veyrat-Durebex C, Bris C, Codron P, Bocca C, Chupin S, Corcia P, Vourc'h P, Hergesheimer R, Cassereau J, Funalot B, Andres CR, Lenaers G, Couratier P, Reynier P, Blasco H<br />
|year=2019<br />
|journal=Mol Neurobiol<br />
|abstract=Amyotrophic lateral sclerosis (ALS) is characterized by a wide metabolic remodeling, as shown by recent metabolomics and lipidomics studies performed in samples from patient cohorts and experimental animal models. Here, we explored the metabolome and lipidome of fibroblasts from sporadic ALS patients (n = 13) comparatively to age- and sex-matched controls (n = 11), and the subcellular fraction containing the mitochondria and endoplasmic reticulum (mito-ER), given that mitochondrial dysfunctions and ER stress are important features of ALS patho-mechanisms. We also assessed the mitochondrial oxidative respiration and the mitochondrial genomic (mtDNA) sequence, although without yielding significant differences. Compared to controls, ALS fibroblasts did not exhibit a mitochondrial respiration defect nor an increased proportion of mitochondrial DNA mutations. In addition, non-targeted metabolomics and lipidomics analyses identified 124 and 127 metabolites, and 328 and 220 lipids in whole cells and the mito-ER fractions, respectively, along with partial least-squares-discriminant analysis (PLS-DA) models being systematically highly predictive of the disease. The most discriminant metabolomic features were the alteration of purine, pyrimidine, and energetic metabolisms, suggestive of oxidative stress and of pro-inflammatory status. The most important lipidomic feature in the mito-ER fraction was the disturbance of phosphatidylcholine PC (36:4p) levels, which we had previously reported in the cerebrospinal fluid of ALS patients and in the brain from an ALS mouse model. Thus, our results reveal that fibroblasts from sporadic ALS patients share common metabolic remodeling, consistent with other metabolic studies performed in ALS, opening perspectives for further exploration in this cellular model in ALS.<br />
|keywords=Amyotrophic lateral sclerosis, Fibroblasts, Lipidomics, Metabolomics, Mitochondria, Oxidative stress<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, Patients<br />
|diseases=Neurodegenerative<br />
|organism=Human<br />
|tissues=Fibroblast<br />
|preparations=Intact cells<br />
|couplingstates=LEAK, ROUTINE, ET<br />
|pathways=ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Ruegsegger_2019_FASEB_J&diff=184288
Ruegsegger 2019 FASEB J
2019-08-12T11:20:40Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Ruegsegger GN, Manjunatha S, Summer P, Gopala S, Zabeilski P, Dasari S, Vanderboom PM, Lanza IR, Klaus KA, Nair KS (2019) Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes. FASEB J 33:4458-72.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30676773 PMID: 30676773]<br />
|authors=Ruegsegger GN, Manjunatha S, Summer P, Gopala S, Zabeilski P, Dasari S, Vanderboom PM, Lanza IR, Klaus KA, Nair KS<br />
|year=2019<br />
|journal=FASEB J<br />
|abstract=Despite the strong association between diabetes and dementia, it remains to be fully elucidated how insulin deficiency adversely affects brain functions. We show that insulin deficiency in streptozotocin-induced diabetic mice decreased mitochondrial ATP production and/or citrate synthase and cytochrome oxidase activities in the cerebrum, hypothalamus, and hippocampus. Concomitant decrease in mitochondrial fusion proteins and increased fission proteins in these brain regions likely contributed to altered mitochondrial function. Although insulin deficiency did not cause any detectable increase in reactive oxygen species (ROS) emission, inhibition of monocarboxylate transporters increased ROS emission and further reduced ATP production, indicating the causative roles of elevated ketones and lactate in counteracting oxidative stress and as a fuel source for ATP production during insulin deficiency. Moreover, in healthy mice, intranasal insulin administration increased mitochondrial ATP production, demonstrating a direct regulatory role of insulin on brain mitochondrial function. Proteomics analysis of the cerebrum showed that although insulin deficiency led to oxidative post-translational modification of several proteins that cause tau phosphorylation and neurofibrillary degeneration, insulin administration enhanced neuronal development and neurotransmission pathways. Together these results render support for the critical role of insulin to maintain brain mitochondrial homeostasis and provide mechanistic insight into the potential therapeutic benefits of intranasal insulin.<br />
|keywords=Ketones, Mitochondrial biogenesis, Proteomics, Reactive oxygen species<br />
|editor=[[Plangger M]],<br />
|mipnetlab=IN Thiruvananthapuram Gopala S, US MN Rochester Nair KS<br />
}}<br />
{{Labeling<br />
|area=Respiration, mt-Biogenesis;mt-density<br />
|diseases=Diabetes<br />
|injuries=Oxidative stress;RONS<br />
|organism=Mouse<br />
|tissues=Nervous system<br />
|preparations=Isolated mitochondria<br />
|topics=ATP production<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N, NS, ROX<br />
|instruments=Oxygraph-2k, O2k-Fluorometer<br />
|additional=2019-01, Amplex Red,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Fisher-Wellman_2019_Cell_Rep&diff=184287
Fisher-Wellman 2019 Cell Rep
2019-08-12T11:18:18Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Fisher-Wellman KH, Draper JA, Davidson MT, Williams AS, Narowski TM, Slentz DH, Ilkayeva OR, Stevens RD, Wagner GR, Najjar R, Hirschey MD, Thompson JW, Olson DP, Kelly DP, Koves TR, Grimsrud PA, Muoio DM (2019) Respiratory phenomics across multiple models of protein hyperacylation in cardiac mitochondria reveals a marginal impact on bioenergetics. Cell Rep 26:1557-72.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30726738 PMID: 30726738 Open Access]<br />
|authors=Fisher-Wellman KH, Draper JA, Davidson MT, Williams AS, Narowski TM, Slentz DH, Ilkayeva OR, Stevens RD, Wagner GR, Najjar R, Hirschey MD, Thompson JW, Olson DP, Kelly DP, Koves TR, Grimsrud PA, Muoio DM<br />
|year=2019<br />
|journal=Cell Rep<br />
|abstract=Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong link between mitochondrial hyperacylation and cardiometabolic diseases; however, the functional consequences of these modifications remain uncertain. Here, we use a comprehensive respiratory diagnostics platform to evaluate three disparate models of mitochondrial hyperacylation in the mouse heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), SIRT5 demalonylase and desuccinylase, or SIRT3 deacetylase. In each case, elevated acylation is accompanied by marginal respiratory phenotypes. Of the >60 mitochondrial energy fluxes evaluated, the only outcome consistently observed across models is a ∼15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that minimally affect mitochondrial bioenergetics.<br />
<br />
<small>Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.</small><br />
|keywords=ATP synthase, Lysine acylation, Malonylation, Mitochondrial diagnostics<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US TN Nashville Wasserman DH, US NC Durham Koves TR<br />
}}<br />
{{Labeling<br />
|area=Respiration, nDNA;cell genetics, Genetic knockout;overexpression<br />
|organism=Mouse<br />
|tissues=Heart, Skeletal muscle<br />
|preparations=Isolated mitochondria<br />
|enzymes=Complex V;ATP synthase<br />
|topics=ATP production, PCr;Cr<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=F, N, S, Gp<br />
|instruments=Oxygraph-2k<br />
|additional=2019-02,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Ma_2018_Nat_Cell_Biol&diff=184286
Ma 2018 Nat Cell Biol
2019-08-12T11:14:12Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Ma C, Niu R, Huang T, Shao LW, Peng Y, Ding W, Wang Y, Jia G, He C, Li CY, He A, Liu Y (2018) N6-methyldeoxyadenine is a transgenerational epigenetic signal for mitochondrial stress adaptation. Nat Cell Biol 21:319-27.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30510156 PMID: 30510156]<br />
|authors=Ma C, Niu R, Huang T, Shao LW, Peng Y, Ding W, Wang Y, Jia G, He C, Li CY, He A, Liu Y<br />
|year=2018<br />
|journal=Nat Cell Biol<br />
|abstract=N6-methyldeoxyadenine (6mA), a major type of DNA methylation in bacteria, represents a part of restriction-modification systems to discriminate host genome from invader DNA[1]. With the recent advent of more sensitive detection techniques, 6mA has also been detected in some eukaryotes[2-8]. However, the physiological function of this epigenetic mark in eukaryotes remains elusive. Heritable changes in DNA 5mC methylation have been associated with transgenerational inheritance of responses to a high-fat diet[9], thus raising the exciting possibility that 6mA may also be transmitted across generations and serve as a carrier of inheritable information. Using ''Caenorhabditis elegans'' as a model, here we report that histone H3K4me3 and DNA 6mA modifications are required for the transmission of mitochondrial stress adaptations to progeny. Intriguingly, the global DNA 6mA level is significantly elevated following mitochondrial perturbation. N6-methyldeoxyadenine marks mitochondrial stress response genes and promotes their transcription to alleviate mitochondrial stress in progeny. These findings suggest that 6mA is a precisely regulated epigenetic mark that modulates stress response and signals transgenerational inheritance in ''C. elegans''.<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, nDNA;cell genetics<br />
|organism=Caenorhabditis elegans<br />
|preparations=Intact cells<br />
|couplingstates=ROUTINE<br />
|instruments=Oxygraph-2k<br />
|additional=2019-02,<br />
}}<br />
== References ==<br />
::::#Heyn H, Esteller M (2015) An adenine code for DNA: a second life for N6-methyladenine. Cell 161:710–13.<br />
::::#Greer EL, Blanco MA, Gu L, Sendinc E, Liu J, Aristizábal-Corrales D, Hsu CH, Aravind L, He C, Shi Y (2015) DNA methylation on N6-adenine in C. elegans. Cell 161:868–78.<br />
::::#Zhang G, Huang H, Liu D, Cheng Y, Liu X, Zhang W, Yin R, Zhang D, Zhang P, Liu J, Li C, Liu B, Luo Y, Zhu Y, Zhang N, He S, He C, Wang H, Chen D (2015) N6-methyladenine DNA modification in Drosophila. Cell 161:893–906.<br />
::::#Koziol MJ, Bradshaw CR, Allen GE, Costa ASH, Frezza C, Gurdon JB (2016) Identification of methylated deoxyadenosines in vertebrates reveals diversity in DNA modifications. Nat Struct Mol Biol 23:24–30.<br />
::::#Wu TP, Wang T, Seetin MG, Lai Y, Zhu S, Lin K, Liu Y, Byrum SD, Mackintosh SG, Zhong M, Tackett A, Wang G, Hon LS, Fang G, Swenberg JA, Xiao AZ (2016) DNA methylation on N(6)-adenine in mammalian embryonic stem cells. Nature 532:329–33.<br />
::::#Liu J, Zhu Y, Luo GZ, Wang X, Yue Y, Wang X, Zong X, Chen K, Yin H, Fu Y, Han D, Wang Y, Chen D, He C (2016) Abundant DNA 6mA methylation during early embryogenesis of zebrafish and pig. Nat Commun 7:13052.<br />
::::#Yao B, Cheng Y, Wang Z, Li Y, Chen L, Huang L, Zhang W, Chen D, Wu H, Tang B, Jin P (2017) DNA N6-methyladenine is dynamically regulated in the mouse brain following environmental stress. Nat Commun 8:1122.<br />
::::#Xiao CL, Zhu S, He M, Chen, Zhang Q, Chen Y, Yu G, Liu J, Xie SQ, Luo F, Liang Z, Wang DP, Bo XC, Gu XF, Wang K, Yan GR (2018) N(6)-methyladenine DNA modification in the human genome. Mol Cell 71:306–18.<br />
::::#Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ (2010) Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467:963–66.</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Cronin_2018_Nature&diff=184265
Cronin 2018 Nature
2019-08-09T11:50:41Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Cronin SJF, Seehus C, Weidinger A, Talbot S, Reissig S, Seifert M, Pierson Y, McNeill E, Longhi MS, Turnes BL, Kreslavsky T, Kogler M, Hoffmann D, Ticevic M, da Luz Scheffer D, Tortola L, Cikes D, Jais A, Rangachari M, Rao S, Paolino M, Novatchkova M, Aichinger M, Barrett L, Latremoliere A, Wirnsberger G, Lametschwandtner G, Busslinger M, Zicha S, Latini A, Robson SC, Waisman A, Andrews N, Costigan M, Channon KM, Weiss G, Kozlov AV, Tebbe M, Johnsson K, Woolf CJ, Penninger JM (2018) The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 563:564-68.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30405245 PMID: 30405245]<br />
|authors=Cronin SJF, Seehus C, Weidinger A, Talbot S, Reissig S, Seifert M, Pierson Y, McNeill E, Longhi MS, Turnes BL, Kreslavsky T, Kogler M, Hoffmann D, Ticevic M, da Luz Scheffer D, Tortola L, Cikes D, Jais A, Rangachari M, Rao S, Paolino M, Novatchkova M, Aichinger M, Barrett L, Latremoliere A, Wirnsberger G, Lametschwandtner G, Busslinger M, Zicha S, Latini A, Robson SC, Waisman A, Andrews N, Costigan M, Channon KM, Weiss G, Kozlov AV, Tebbe M, Johnsson K, Woolf CJ, Penninger JM<br />
|year=2018<br />
|journal=Nature<br />
|abstract=Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain<sup>1,2</sup>. Here we uncover a link between these processes, identifying a fundamental role for BH4 in T cell biology. We find that genetic inactivation of GTP cyclohydrolase 1 (GCH1, the rate-limiting enzyme in the synthesis of BH4) and inhibition of sepiapterin reductase (the terminal enzyme in the synthetic pathway for BH4) severely impair the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. ''In vivo'' blockade of BH4 synthesis abrogates T-cell-mediated autoimmunity and allergic inflammation, and enhancing BH4 levels through GCH1 overexpression augments responses by CD4- and CD8-expressing T cells, increasing their antitumour activity ''in vivo''. Administration of BH4 to mice markedly reduces tumour growth and expands the population of intratumoral effector T cells. Kynurenine-a tryptophan metabolite that blocks antitumour immunity-inhibits T cell proliferation in a manner that can be rescued by BH4. Finally, we report the development of a potent SPR antagonist for possible clinical use. Our data uncover GCH1, SPR and their downstream metabolite BH4 as critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity.<br />
|editor=[[Plangger M]],<br />
|mipnetlab=AT Vienna Kozlov AV, BR Florianapolis Latini A<br />
}}<br />
{{Labeling<br />
|area=Respiration, Genetic knockout;overexpression<br />
|diseases=Cancer<br />
|organism=Mouse<br />
|tissues=Lymphocyte<br />
|preparations=Permeabilized cells, Intact cells<br />
|couplingstates=LEAK, ROUTINE, OXPHOS, ET<br />
|pathways=N, S<br />
|instruments=Oxygraph-2k<br />
|additional=2018-11,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Bajzikova_2019_Cell_Metab&diff=184264
Bajzikova 2019 Cell Metab
2019-08-09T11:46:38Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Bajzikova M, Kovarova J, Coelho AR, Boukalova S, Oh S, Rohlenova K, Svec D, Hubackova S, Endaya B, Judasova K, Bezawork-Geleta A, Kluckova K, Chatre L, Zobalova R, Novakova A, Vanova K, Ezrova Z, Maghzal GJ, Magalhaes Novais S, Olsinova M, Krobova L, An YJ, Davidova E, Nahacka Z, Sobol M, Cunha-Oliveira T, Sandoval-Acuña C, Strnad H, Zhang T, Huynh T, Serafim TL, Hozak P, Sardao VA, Koopman WJH, Ricchetti M, Oliveira PJ, Kolar F, Kubista M, Truksa J, Dvorakova-Hortova K, Pacak K, Gurlich R, Stocker R, Zhou Y, Berridge MV, Park S, Dong L, Rohlena J, Neuzil J (2019) Reactivation of dihydroorotate dehydrogenase-driven pyrimidine biosynthesis restores tumor growth of respiration-deficient cancer cells. Cell Metab 29:399-416.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30449682 PMID: 30449682]<br />
|authors=Bajzikova M, Kovarova J, Coelho AR, Boukalova S, Oh S, Rohlenova K, Svec D, Hubackova S, Endaya B, Judasova K, Bezawork-Geleta A, Kluckova K, Chatre L, Zobalova R, Novakova A, Vanova K, Ezrova Z, Maghzal GJ, Magalhaes Novais S, Olsinova M, Krobova L, An YJ, Davidova E, Nahacka Z, Sobol M, Cunha-Oliveira T, Sandoval-Acuna C, Strnad H, Zhang T, Huynh T, Serafim TL, Hozak P, Sardao VA, Koopman WJH, Ricchetti M, Oliveira PJ, Kolar F, Kubista M, Truksa J, Dvorakova-Hortova K, Pacak K, Gurlich R, Stocker R, Zhou Y, Berridge MV, Park S, Dong L, Rohlena J, Neuzil J<br />
|year=2019<br />
|journal=Cell Metab<br />
|abstract=Cancer cells without mitochondrial DNA (mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA-depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with restoration of complex III/IV activity and coenzyme Q redox-cycling after mitochondrial transfer, or by introduction of an alternative oxidase. Further, deletion of DHODH interferes with tumor formation in cells with fully functional OXPHOS, while disruption of mitochondrial ATP synthase has little effect. Our results show that DHODH-driven pyrimidine biosynthesis is an essential pathway linking respiration to tumorigenesis, pointing to inhibitors of DHODH as potential anti-cancer agents.<br />
|keywords=OXPHOS, Cancer, Coenzyme Q, Dihydroorotate dehydrogenase, Mitochondria, Pyrimidine biosynthesis, Respiration<br />
|editor=[[Plangger M]]<br />
|mipnetlab=CZ Prague Neuzil J, AU Queensland Neuzil J, NL Nijmegen Koopman WJ, AU Sydney Stocker R, AU Queensland Peart J<br />
}}<br />
{{Labeling<br />
|area=Respiration, Genetic knockout;overexpression<br />
|diseases=Cancer<br />
|organism=Mouse<br />
|tissues=Endothelial;epithelial;mesothelial cell, Genital, Other cell lines<br />
|preparations=Permeabilized cells, Homogenate<br />
|enzymes=Complex I, Complex II;succinate dehydrogenase, Complex III, Complex V;ATP synthase<br />
|couplingstates=OXPHOS, ET<br />
|pathways=N, S, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2018-11, PBI-Shredder,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Konopka_2018_Aging_Cell&diff=184257
Konopka 2018 Aging Cell
2019-08-09T11:34:20Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Konopka AR, Laurin JL, Schoenberg HM, Reid JJ, Castor WM, Wolff CA, Musci RV, Safairad OD, Linden MA, Biela LM, Bailey SM, Hamilton KL, Miller BF (2018) Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell 18:e12880.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30548390 PMID: 30548390 Open Access]<br />
|authors=Konopka AR, Laurin JL, Schoenberg HM, Reid JJ, Castor WM, Wolff CA, Musci RV, Safairad OD, Linden MA, Biela LM, Bailey SM, Hamilton KL, Miller BF<br />
|year=2018<br />
|journal=Aging Cell<br />
|abstract=Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double-blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24-hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole-body insulin sensitivity and VO<sub>2</sub> max after AET. In the metformin group, there was no overall change in whole-body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration. The change in whole-body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET-induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.<br />
|keywords=Aging, Healthspan, Protein synthesis, Proteostasis, Telomere<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US IL Urbana Konopka, US CO Fort Collins Hamilton K<br />
}}<br />
{{Labeling<br />
|area=Respiration, Exercise physiology;nutrition;life style, Pharmacology;toxicology<br />
|diseases=Aging;senescence, Diabetes<br />
|organism=Human<br />
|tissues=Skeletal muscle<br />
|preparations=Permeabilized tissue<br />
|topics=ADP<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=F, N, S, NS, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2018-12,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Hirschi_2019_Biol_Reprod&diff=184256
Hirschi 2019 Biol Reprod
2019-08-09T11:27:18Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Hirschi KM, Tsai KYF, Davis T, Clark JC, Knowlton MN, Bikman BT, Reynolds PR, Arroyo JA (2019) Growth arrest specific protein (Gas)-6/AXL signaling induces preeclampsia (PE) in rats. Biol Reprod [Epub ahead of print].<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/31347670 PMID: 31347670]<br />
|authors=Hirschi KM, Tsai KYF, Davis T, Clark JC, Knowlton MN, Bikman BT, Reynolds PR, Arroyo JA<br />
|year=2019<br />
|journal=Biol Reprod<br />
|abstract=Preeclampsia (PE) is a complicated obstetric complication characterized by increased blood pressure, decreased trophoblast invasion, and inflammation. The growth arrest-specific 6 (Gas6) protein is known to induce dynamic cellular responses and is elevated in PE. Gas6 binds to the AXL tyrosine kinase receptor and AXL-mediated signaling is implicated in proliferation and migration observed in several tissues. Our laboratory utilized Gas6 to induce preeclamptic-like conditions in pregnant rats. Our objective was to determine the role of Gas6/AXL signaling as a possible model of PE. Briefly, pregnant rats were divided into 3 groups that received daily intraperitoneal injections (from gestational day 7.5-17.5) of PBS, Gas6, or Gas6 + R428 (an AXL inhibitor administered from gestational day 13.5-17.5). Animals dispensed Gas6 experienced elevated blood pressure, increased proteinuria, augmented caspase-3 mediated placental apoptosis and diminished trophoblast invasion. Gas6 also enhanced expression of several PE related genes and a number of inflammatory mediators. Gas6 further enhanced placental oxidative stress and impaired mitochondrial respiration. Each of these PE related characteristics were ameliorated in dams and/or their placentae when AXL inhibition by R428 occurred in tandem with Gas6 treatment. We conclude that Gas6 signaling is capable of inducing PE and that inhibition of AXL prevents disease progression in pregnant rats. These results provide insight into pathways associated with PE that could be useful in the clarification of potential therapeutic approaches.<br />
<br />
<small>© The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction.</small><br />
|keywords=AXL, Gas6, Placenta, Preeclampsia<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US UT Provo Bikman BT<br />
}}<br />
{{Labeling<br />
|area=Respiration, Pharmacology;toxicology<br />
|diseases=Other<br />
|organism=Rat<br />
|tissues=Genital<br />
|preparations=Permeabilized cells, Permeabilized tissue<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=N, S, NS<br />
|instruments=Oxygraph-2k<br />
|additional=2019-08,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Dela_2018_Acta_Physiol_(Oxf)&diff=184254
Dela 2018 Acta Physiol (Oxf)
2019-08-09T10:52:08Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Dela F, Ingersen A, Andersen NB, Nielsen MB, Petersen HHH, Hansen CN, Larsen S, Wojtaszewski J, Helge JW (2018) Effects of one-legged high-intensity interval training on insulin-mediated skeletal muscle glucose homeostasis in patients with type 2 diabetes. Acta Physiol (Oxf) 226:e13245.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30585698 PMID: 30585698]<br />
|authors=Dela F, Ingersen A, Andersen NB, Nielsen MB, Petersen HHH, Hansen CN, Larsen S, Wojtaszewski J, Helge JW<br />
|year=2018<br />
|journal=Acta Physiol (Oxf)<br />
|abstract=To examine the effect of high-intensity interval training (HIIT) on glucose clearance rates in skeletal muscle and explore the mechanism within the muscle.<br />
<br />
Ten males with type 2 diabetes mellitus (T2DM) and ten matched healthy subjects performed 2 weeks of one-legged HIIT (total of eight sessions, each comprised of 10 x 1 min ergometer bicycle exercise at > 80% of maximal heart rate, interspersed with one min of rest). Insulin sensitivity was assessed by an isoglycemic, hyperinsulinemic clamp combined with arterio-venous leg balance technique of the trained (T) and the untrained (UT) leg and muscle biopsies of both legs.<br />
<br />
Insulin stimulated glucose clearance in T legs were ~30% higher compared with UT legs in both groups due to increased blood flow in T vs. UT legs and maintained glucose extraction. With each training session muscle glycogen content decreased only in the training leg and after the training glycogen synthase and citrate synthase activities were higher in T vs. UT legs. No major changes occurred in the expression of proteins in the insulin signaling cascade. Mitochondrial respiratory capacity was similar in T2DM and healthy subjects, and unchanged by HIIT.<br />
<br />
HIIT improves skeletal muscle insulin sensitivity. With HIIT, the skeletal muscle of patients with T2DM becomes just as insulin sensitive as untrained muscle in healthy subjects. The mechanism include oscillations in muscle glycogen stores and a maintained ability to extract glucose from the blood in the face of increased blood flow in the trained leg. This article is protected by copyright.<br />
<br />
<small>This article is protected by copyright. All rights reserved.</small><br />
|keywords=Diabetes mellitus, Glucose metabolism, Leg balance, Overweight<br />
|editor=[[Plangger M]],<br />
|mipnetlab=DK Copenhagen Dela F, DK Copenhagen Larsen S<br />
}}<br />
{{Labeling<br />
|area=Respiration, Exercise physiology;nutrition;life style<br />
|diseases=Diabetes<br />
|organism=Human<br />
|tissues=Skeletal muscle<br />
|preparations=Permeabilized tissue<br />
|enzymes=Complex III<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N, NS, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Abdelwahab_2018_Oncogene&diff=184253
Abdelwahab 2018 Oncogene
2019-08-09T10:32:49Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Abdelwahab EMM, Pal S, Kvell K, Sarosi V, Bai P, Rue R, Krymskaya V, McPhail D, Porter A, Pongracz JE (2018) Mitochondrial dysfunction is a key determinant of the rare disease lymphangioleiomyomatosis and provides a novel therapeutic target. Oncogene 38:3093-3101.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30573768 PMID: 30573768 Open Access]<br />
|authors=Abdelwahab EMM, Pal S, Kvell K, Sarosi V, Bai P, Rue R, Krymskaya V, McPhail D, Porter A, Pongracz JE<br />
|year=2018<br />
|journal=Oncogene<br />
|abstract=Lymphangioleiomyomatosis (LAM) is a rare and progressive systemic disease affecting mainly young women of childbearing age. A deterioration in lung function is driven by neoplastic growth of atypical smooth muscle-like LAM cells in the pulmonary interstitial space that leads to cystic lung destruction and spontaneous pneumothoraces. Therapeutic options for preventing disease progression are limited and often end with lung transplantation temporarily delaying an inevitable decline. To identify new therapeutic strategies for this crippling orphan disease, we have performed array based and metabolic molecular analysis on patient-derived cell lines. Our results point to the conclusion that mitochondrial biogenesis and mitochondrial dysfunction in LAM cells provide a novel target for treatment.<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, mtDNA;mt-genetics, nDNA;cell genetics, Pharmacology;toxicology<br />
|diseases=Other<br />
|organism=Human<br />
|tissues=Lung;gill, Endothelial;epithelial;mesothelial cell<br />
|preparations=Intact cells<br />
|couplingstates=ROUTINE<br />
|pathways=ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Lefranc_2019_Hypertension&diff=184252
Lefranc 2019 Hypertension
2019-08-09T10:27:05Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Lefranc C, Friederich-Persson M, Braud L, Palacios-Ramirez R, Karlsson S, Boujardine N, Motterlini R, Jaisser F, Nguyen Dinh Cat A (2019) MR (mineralocorticoid receptor) induces adipose tissue senescence and mitochondrial dysfunction leading to vascular dysfunction in obesity. Hypertension 73:458-68.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30624990 PMID: 30624990]<br />
|authors=Lefranc C, Friederich-Persson M, Braud L, Palacios-Ramirez R, Karlsson S, Boujardine N, Motterlini R, Jaisser F, Nguyen Dinh Cat A<br />
|year=2019<br />
|journal=Hypertension<br />
|abstract=Adipose tissue (AT) senescence and mitochondrial dysfunction are associated with obesity. Studies in obese patients and animals demonstrate that the MR (mineralocorticoid receptor) contributes to obesity-associated cardiovascular complications through its specific role in AT. However, underlying mechanisms remain unclear. This study aims to elucidate whether MR regulates mitochondrial function in obesity, resulting in AT premature aging and vascular dysfunction. Obese (db/db) and lean (db/+) mice were treated with an MR antagonist or a specific mitochondria-targeted antioxidant. Mitochondrial and vascular functions were determined by respirometry and myography, respectively. Molecular mechanisms were probed by Western immunoblotting and real-time polymerase chain reaction in visceral AT and arteries and focused on senescence markers and redox-sensitive pathways. db/db mice displayed AT senescence with activation of the p53-p21 pathway and decreased SIRT (sirtuin) levels, as well as mitochondrial dysfunction. Furthermore, the beneficial anticontractile effects of perivascular AT were lost in db/db via ROCK (Rho kinase) activation. MR blockade prevented these effects. Thus, MR activation in obesity induces mitochondrial dysfunction and AT senescence and dysfunction, which consequently increases vascular contractility. In conclusion, our study identifies novel mechanistic insights involving MR, adipose mitochondria, and vascular function that may be of importance to develop new therapeutic strategies to limit obesity-associated cardiovascular complications.<br />
|keywords=Adipose tissue, Aging, Mitochondria, Obesity, Oxidative stress, Sirtuins, Vasoconstriction<br />
|editor=[[Plangger M]],<br />
|mipnetlab=SE Uppsala Liss P<br />
}}<br />
{{Labeling<br />
|area=Respiration, Pharmacology;toxicology<br />
|diseases=Aging;senescence, Obesity<br />
|organism=Mouse<br />
|tissues=Fat<br />
|preparations=Isolated mitochondria<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N<br />
|instruments=Oxygraph-2k, O2k-Fluorometer<br />
|additional=2019-01, Amplex UltraRed,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Jumbo-Lucioni_2012_BMC_Genomics&diff=184251
Jumbo-Lucioni 2012 BMC Genomics
2019-08-09T10:21:04Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Jumbo-Lucioni P, Bu S, Harbison ST, Slaughter JC, Mackay TF, Moellering DR, De Luca M (2012) Nuclear genomic control of naturally occurring variation in mitochondrial function in ''Drosophila melanogaster''. BMC Genomics 13:659.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/23171078 PMID: 23171078 Open Access]<br />
|authors=Jumbo-Lucioni P, Bu S, Harbison ST, Slaughter JC, Mackay TF, Moellering DR, De Luca M<br />
|year=2012<br />
|journal=BMC Genomics<br />
|abstract=Mitochondria are organelles found in nearly all eukaryotic cells that play a crucial role in cellular survival and function. Mitochondrial function is under the control of nuclear and mitochondrial genomes. While the latter has been the focus of most genetic research, we remain largely ignorant about the nuclear-encoded genomic control of inter-individual variability in mitochondrial function. Here, we used ''Drosophila melanogaster'' as our model organism to address this question.<br />
<br />
We quantified mitochondrial state 3 and state 4 respiration rates and P:O ratio in mitochondria isolated from the thoraces of 40 sequenced inbred lines of the Drosophila Genetic Reference Panel. We found significant within-population genetic variability for all mitochondrial traits. Hence, we performed genome-wide association mapping and identified 141 single nucleotide polymorphisms (SNPs) associated with differences in mitochondrial respiration and efficiency (P ≤1 × 10<sup>-5</sup>). Gene-centered regression models showed that 2-3 SNPs can explain 31, 13, and 18% of the phenotypic variation in state 3, state 4, and P:O ratio, respectively. Most of the genes tagged by the SNPs are involved in organ development, second messenger-mediated signaling pathways, and cytoskeleton remodeling. One of these genes, ''sallimus'' (''sls''), encodes a component of the muscle sarcomere. We confirmed the direct effect of ''sls'' on mitochondrial respiration using two viable mutants and their coisogenic wild-type strain. Furthermore, correlation network analysis revealed that ''sls'' functions as a transcriptional hub in a co-regulated module associated with mitochondrial respiration and is connected to CG7834, which is predicted to encode a protein with mitochondrial electron transfer flavoprotein activity. This latter finding was also verified in the ''sls'' mutants.<br />
<br />
Our results provide novel insights into the genetic factors regulating natural variation in mitochondrial function in ''D. melanogaster''. The integrative genomic approach used in our study allowed us to identify ''sls'' as a novel hub gene responsible for the regulation of mitochondrial respiration in muscle sarcomere and to provide evidence that ''sls'' might act via the electron transfer flavoprotein/ubiquinone oxidoreductase complex.<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US AL Birmingham Moellering DR<br />
}}<br />
{{Labeling<br />
|area=Respiration, nDNA;cell genetics<br />
|organism=Drosophila<br />
|tissues=Skeletal muscle<br />
|preparations=Isolated mitochondria<br />
|couplingstates=LEAK, OXPHOS<br />
|pathways=N<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Farias_2018_Int_J_Biol_Macromol&diff=184250
Farias 2018 Int J Biol Macromol
2019-08-09T10:15:36Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Farias CLA, Martinez GR, Cadena SMSC, Mercê ALR, de Oliveira Petkowicz CL, Noleto GR (2018) Cytotoxicity of xyloglucan from ''Copaifera langsdorffii'' and its complex with oxovanadium (IV/V) on B16F10 cells. Int J Biol Macromol 121:1019-28.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30340004 PMID: 30340004 Open Access]<br />
|authors=Farias CLA, Martinez GR, Cadena SMSC, Merce ALR, de Oliveira Petkowicz CL, Noleto GR<br />
|year=2018<br />
|journal=Int J Biol Macromol<br />
|abstract=The aim of this study was to investigate the effects of xyloglucan extracted from ''Copaifera langsdorffii'' seeds (XGC) and its complex with oxovanadium (XGC:VO) in murine melanoma B16F10 cells. The formation of complexes was followed by potentiometric titration and further demonstrated by <sup>51</sup>V RMN. The viability and proliferation of B16F10 cells were reduced up 50% by the xyloglucan and its complex, both at 200 μg/mL, from 24 to 72 h. Cytotoxic effects of XGC and XGC:VO do not involve changes in cell cycle progression. Only XGC:VO (200 μg/mL) promoted the cell death evidenced by annexin V stain. XGC increased the respiration and lactate levels in melanoma cells, while XGC:VO reduced about 50% the respiration and levels of pyruvate, without alter the lactate levels, indicating that both xyloglucan preparations interfere with the metabolism of B16F10 cells. No change in activity of the enzyme hexokinase and expression of pyruvate kinase M2 was observed. XGC:VO (200 μg/mL) negatively modulated the expression of the β subunit of ATP synthase. The results demonstrate that the cytotoxicity of XGC and XGC:VO on murine melanoma B16F10 cells can be related to the impairment of the mitochondrial functions linked to energy provision.<br />
<br />
<small>Copyright © 2018. Published by Elsevier B.V.</small><br />
|keywords=B16F10 mouse skin melanoma cells, Melanoma, Metal complexes, Oxovanadium, Polysaccharides, Xyloglucan<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, Pharmacology;toxicology<br />
|organism=Mouse<br />
|tissues=Endothelial;epithelial;mesothelial cell<br />
|preparations=Intact cells<br />
|couplingstates=LEAK, ROUTINE, ET<br />
|pathways=ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Oliveira_2019_Mol_Nutr_Food_Res&diff=184249
Oliveira 2019 Mol Nutr Food Res
2019-08-09T10:07:34Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Oliveira TE, Castro É, Belchior T, Andrade ML, Chaves-Filho AB, Peixoto AS, Moreno MF, Ortiz Silva M, Moreira RJ, Inague A, Yoshinaga MY, Miyamoto S, Moustaid-Moussa N, Festuccia WT (2019) Fish oil protects wild type and uncoupling protein 1 deficient mice from obesity and glucose intolerance by increasing energy expenditure. Mol Nutr Food Res 63:e1800813.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30632684 PMID: 30632684]<br />
|authors=Oliveira TE, Castro E, Belchior T, Andrade ML, Chaves-Filho AB, Peixoto AS, Moreno MF, Ortiz Silva M, Moreira RJ, Inague A, Yoshinaga MY, Miyamoto S, Moustaid-Moussa N, Festuccia WT<br />
|year=2019<br />
|journal=Mol Nutr Food Res<br />
|abstract=We investigated the mechanisms and involvement of uncoupling protein 1 (UCP1) in the protection from obesity and insulin resistance induced by intake of high-fat diet rich in omega 3 (n-3) fatty acids.<br />
<br />
C57BL/6J mice were fed either a low-fat (control group) or one of two isocaloric high-fat diets containing either lard (HFD) or fish oil (HFN3) as fat source and evaluated for body weight, adiposity, energy expenditure, glucose homeostasis and inguinal white and interscapular brown adipose tissues (iWAT and iBAT, respectively) gene expression, lipidome and mitochondrial bioenergetics. HFN3 intake protected from obesity, glucose and insulin intolerances and hyperinsulinemia. This was associated with increased energy expenditure, iWAT UCP1 expression and incorporation of n-3 eicosapentaenoic and docosahexaenoic fatty acids in iWAT and iBAT triacylglycerol. Importantly, HFN3 was equally effective in reducing body weight gain, adiposity and glucose intolerance and increasing energy expenditure in wild type and UCP1-deficient mice without recruiting other thermogenic processes in iWAT and iBAT such as mitochondrial uncoupling, SERCA-mediated calcium and creatine-driven substrate cyclings.<br />
<br />
Intake of a high-fat diet rich in omega 3 fatty acids protects both wild type and UCP1-deficient mice from obesity and insulin resistance by increasing energy expenditure through unknown mechanisms.<br />
<br />
<small>This article is protected by copyright. All rights reserved.</small><br />
|keywords=Cardiolipin, Energy expenditure, Fish oil, Nonshivering thermogenesis, Obesity, Omega 3 fatty acids, Uncoupling protein 1, White and brown adipose tissues<br />
|editor=[[Plangger M]],<br />
|mipnetlab=BR Sao Paulo Festuccia W<br />
}}<br />
{{Labeling<br />
|area=Respiration, Exercise physiology;nutrition;life style<br />
|diseases=Obesity<br />
|organism=Mouse<br />
|tissues=Fat<br />
|preparations=Isolated mitochondria<br />
|enzymes=Uncoupling protein<br />
|topics=Fatty acid<br />
|couplingstates=LEAK, ET<br />
|pathways=N<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=D%27Amico_2019_Mol_Cell&diff=184248
D'Amico 2019 Mol Cell
2019-08-09T10:04:02Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=D'Amico D, Mottis A, Potenza F, Sorrentino V, Li H, Romani M, Lemos V, Schoonjans K, Zamboni N, Knott G, Schneider BL, Auwerx J (2019) The RNA-binding protein PUM2 impairs mitochondrial dynamics and mitophagy during aging. Mol Cell 73:775-87.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30642763 PMID: 30642763]<br />
|authors=D'Amico D, Mottis A, Potenza F, Sorrentino V, Li H, Romani M, Lemos V, Schoonjans K, Zamboni N, Knott G, Schneider BL, Auwerx J<br />
|year=2019<br />
|journal=Mol Cell<br />
|abstract=Little information is available about how post-transcriptional mechanisms regulate the aging process. Here, we show that the RNA-binding protein Pumilio2 (PUM2), which is a translation repressor, is induced upon aging and acts as a negative regulator of lifespan and mitochondrial homeostasis. Multi-omics and cross-species analyses of PUM2 function show that it inhibits the translation of the mRNA encoding for the mitochondrial fission factor (''Mff''), thereby impairing mitochondrial fission and mitophagy. This mechanism is conserved in ''C. elegans'' by the PUM2 ortholog PUF-8. ''puf-8'' knock-down in old nematodes and Pum2 CRISPR/Cas9-mediated knockout in the muscles of elderly mice enhances mitochondrial fission and mitophagy in both models, hence improving mitochondrial quality control and tissue homeostasis. Our data reveal how a PUM2-mediated layer of post-transcriptional regulation links altered ''Mff'' translation to mitochondrial dynamics and mitophagy, thereby mediating age-related mitochondrial dysfunctions.<br />
<br />
<small>Copyright © 2018 Elsevier Inc. All rights reserved.</small><br />
|keywords=RNA binding proteins, Aging, Fission/fusion, Mitochondria, Mitochondrial dynamics, Mitophagy, Neurodegeneration, Protein aggregation diseases, Proteostasis, Ribonucleoprotein granules<br />
|editor=[[Plangger M]],<br />
|mipnetlab=CH Lausanne Auwerx J<br />
}}<br />
{{Labeling<br />
|area=Respiration, Genetic knockout;overexpression<br />
|diseases=Aging;senescence<br />
|organism=Mouse<br />
|tissues=Skeletal muscle<br />
|preparations=Homogenate<br />
|couplingstates=OXPHOS<br />
|pathways=S, NS, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Zhu_2019_Aging_Cell&diff=184246
Zhu 2019 Aging Cell
2019-08-09T09:50:38Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Zhu B, Li Y, Xiang L, Zhang J, Wang L, Guo B, Liang M, Chen L, Xiang L, Dong J, Liu M, Mei W, Li H, Xiang G (2019) Alogliptin improves survival and health of mice on a high-fat diet. Aging Cell 18:e12883.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30644630 PMID: 30644630 Open Access]<br />
|authors=Zhu B, Li Y*, Xiang L, Zhang J*, Wang L, Guo B, Liang M, Chen L, Xiang L, Dong J, Liu M, Mei W, Li H, Xiang G<br />
|year=2019<br />
|journal=Aging Cell<br />
|abstract=Alogliptin is a commonly prescribed drug treating patients with type 2 diabetes. Here, we show that long-term intervention with alogliptin (0.03% w/w in diet) improves survival and health of mice on a high-fat diet. Alogliptin intervention takes beneficial effects associated with longevity, including increased insulin sensitivity, attenuated functionality decline, decreased organ pathology, preserved mitochondrial function, and reduced oxidative stress. Autophagy activation is proposed as an underlying mechanism of these beneficial effects. We conclude that alogliptin intervention could be considered as a potential strategy for extending lifespan and healthspan in obesity and overweight.<br />
<br />
<small>© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.</small><br />
|keywords=DPP-4 inhibitor, GLP-1, Healthspan, High-fat diet, Longevity<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, Exercise physiology;nutrition;life style, Pharmacology;toxicology<br />
|diseases=Aging;senescence, Diabetes<br />
|organism=Mouse<br />
|tissues=Liver<br />
|preparations=Isolated mitochondria<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=N, S, NS, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Bettinazzi_2019_Proc_Biol_Sci&diff=184244
Bettinazzi 2019 Proc Biol Sci
2019-08-09T09:40:03Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Bettinazzi S, Rodríguez E, Milani L, Blier PU, Breton S (2019) Metabolic remodelling associated with mtDNA: insights into the adaptive value of doubly uniparental inheritance of mitochondria. Proc Biol Sci 286:20182708.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30963924 PMID: 30963924 Open Access]<br />
|authors=Bettinazzi S, Rodriguez E, Milani L, Blier PU, Breton S<br />
|year=2019<br />
|journal=Proc Biol Sci<br />
|abstract=Mitochondria produce energy through oxidative phosphorylation (OXPHOS), which depends on the expression of both nuclear and mitochondrial DNA (mtDNA). In metazoans, a striking exception from strictly maternal inheritance of mitochondria is doubly uniparental inheritance (DUI). This unique system involves the maintenance of two highly divergent mtDNAs (F- and M-type, 8–40% of nucleotide divergence) associated with gametes, and occasionally coexisting in somatic tissues. To address whether metabolic differences underlie this condition, we characterized the OXPHOS activity of oocytes, spermatozoa, and gills of different species through respirometry. DUI species express different gender-linked mitochondrial phenotypes in gametes and partly in somatic tissues. The M-phenotype is specific to sperm and entails (i) low coupled/uncoupled respiration rates, (ii) a limitation by the phosphorylation system, and (iii) a null excess capacity of the final oxidases, supporting a strong control over the upstream complexes. To our knowledge, this is the first example of a phenotype resulting from direct selection on sperm mitochondria. This metabolic remodelling suggests an adaptive value of mtDNA variations and we propose that bearing sex-linked mitochondria could assure the energetic requirements of different gametes, potentially linking male-energetic adaptation, mitotype preservation and inheritance, as well as resistance to both heteroplasmy and ageing.<br />
|keywords=Mitochondria, Oxidative phosphorylation, Doubly uniparental inheritance, Heteroplasmy, Ageing, Mito-nuclear coevolution<br />
|editor=[[Plangger M]],<br />
|mipnetlab=CA Montreal Breton S, CA Rimouski Blier PU<br />
}}<br />
{{Labeling<br />
|area=Respiration, mtDNA;mt-genetics, Comparative MiP;environmental MiP, Gender<br />
|organism=Molluscs<br />
|tissues=Lung;gill, Genital<br />
|preparations=Permeabilized cells<br />
|topics=Flux control<br />
|couplingstates=LEAK, OXPHOS, ET<br />
|pathways=N, Gp, CIV, NS, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-02,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Mann_2019_Oncogene&diff=184230
Mann 2019 Oncogene
2019-08-09T09:15:02Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Mann J, Githaka JM, Buckland TW, Yang N, Montpetit R, Patel N, Li L, Baksh S, Godbout R, Lemieux H, Goping IS (2019) Non-canonical BAD activity regulates breast cancer cell and tumor growth via 14-3-3 binding and mitochondrial metabolism. Oncogene 38:3325-39.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/30635657 PMID: 30635657 Open Access]<br />
|authors=Mann J, Githaka JM, Buckland TW, Yang N, Montpetit R, Patel N, Li L, Baksh S, Godbout R, Lemieux H, Goping IS<br />
|year=2019<br />
|journal=Oncogene<br />
|abstract=The Bcl-2-associated death promoter BAD is a prognostic indicator for good clinical outcome of breast cancer patients; however, whether BAD affects breast cancer biology is unknown. Here we showed that BAD increased cell growth in breast cancer cells through two distinct mechanisms. Phosphorylation of BAD at S118 increased S99 phosphorylation, 14-3-3 binding and AKT activation to promote growth and survival. Through a second, more prominent pathway, BAD stimulated mitochondrial oxygen consumption in a novel manner that was downstream of substrate entry into the mitochondria. BAD stimulated complex I activity that facilitated enhanced cell growth and sensitized cells to apoptosis in response to complex I blockade. We propose that this dependence on oxidative metabolism generated large but nonaggressive cancers. This model identifies a non-canonical role for BAD and reconciles BAD-mediated tumor growth with favorable outcomes in BAD-high breast cancer patients.<br />
|keywords=MDA-MB-231 human breast cancer cells, MCF10A human breast cancer cells<br />
|editor=[[Plangger M]],<br />
|mipnetlab=CA Edmonton Lemieux H<br />
}}<br />
{{Labeling<br />
|area=Respiration, nDNA;cell genetics<br />
|diseases=Cancer<br />
|injuries=Cell death<br />
|organism=Human<br />
|tissues=Endothelial;epithelial;mesothelial cell<br />
|preparations=Permeabilized cells, Intact cells<br />
|enzymes=Complex I<br />
|couplingstates=LEAK, ROUTINE, OXPHOS, ET<br />
|pathways=F, N, S, CIV, NS, ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-01,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Andreazza_2019_Nat_Commun&diff=184227
Andreazza 2019 Nat Commun
2019-08-09T08:40:07Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Andreazza S, Samstag CL, Sanchez-Martinez A, Fernandez-Vizarra E, Gomez-Duran A, Lee JJ, Tufi R, Hipp MJ, Schmidt EK, Nicholls TJ, Gammage PA, Chinnery PF, Minczuk M, Pallanck LJ, Kennedy SR, Whitworth AJ (2019) Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila. Nat Commun 10:3280.<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/31337756 PMID: 31337756 Open Access]<br />
|authors=Andreazza S, Samstag CL, Sanchez-Martinez A, Fernandez-Vizarra E, Gomez-Duran A, Lee JJ, Tufi R, Hipp MJ, Schmidt EK, Nicholls TJ, Gammage PA, Chinnery PF, Minczuk M, Pallanck LJ, Kennedy SR, Whitworth AJ<br />
|year=2019<br />
|journal=Nat Commun<br />
|abstract=Somatic mutations in the mitochondrial genome (mtDNA) have been linked to multiple disease conditions and to ageing itself. In ''Drosophila'', knock-in of a proofreading deficient mtDNA polymerase (POLG) generates high levels of somatic point mutations and also small indels, but surprisingly limited impact on organismal longevity or fitness. Here we describe a new mtDNA mutator model based on a mitochondrially-targeted cytidine deaminase, APOBEC1. ''mito''-APOBEC1 acts as a potent mutagen which exclusively induces C:G>T:A transitions with no indels or mtDNA depletion. In these flies, the presence of multiple non-synonymous substitutions, even at modest heteroplasmy, disrupts mitochondrial function and dramatically impacts organismal fitness. A detailed analysis of the mutation profile in the POLG and ''mito''-APOBEC1 models reveals that mutation type (quality) rather than quantity is a critical factor in impacting organismal fitness. The specificity for transition mutations and the severe phenotypes make ''mito''-APOBEC1 an excellent mtDNA mutator model for ageing research.<br />
|editor=[[Plangger M]],<br />
}}<br />
{{Labeling<br />
|area=Respiration, mtDNA;mt-genetics, Genetic knockout;overexpression<br />
|organism=Drosophila<br />
|preparations=Homogenate<br />
|couplingstates=OXPHOS<br />
|pathways=N, S<br />
|instruments=Oxygraph-2k<br />
|additional=2019-08,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Fink_2019_FASEB_J&diff=184226
Fink 2019 FASEB J
2019-08-09T08:37:45Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Fink BD, Yu L, Sivitz WI (2019) Modulation of complex II-energized respiration in muscle, heart, and brown adipose mitochondria by oxaloacetate and complex I electron flow. FASEB J [Epub ahead of print].<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/31361970 PMID: 31361970]<br />
|authors=Fink BD, Yu L, Sivitz WI<br />
|year=2019<br />
|journal=FASEB J<br />
|abstract=We recently reported that membrane potential (ΔΨ) primarily determines the relationship of complex II-supported respiration by isolated skeletal muscle mitochondria to ADP concentrations. We observed that O2 flux peaked at low ADP concentration ([ADP]) (high ΔΨ) before declining at higher [ADP] (low ΔΨ). The decline resulted from oxaloacetate (OAA) accumulation and inhibition of succinate dehydrogenase. This prompted us to question the effect of incremental [ADP] on respiration in interscapular brown adipose tissue (IBAT) mitochondria, wherein ΔΨ is intrinsically low because of uncoupling protein 1 (UCP1). We found that succinate-energized IBAT mitochondria, even in the absence of ADP, accumulate OAA and manifest limited respiration, similar to muscle mitochondria at high [ADP]. This could be prevented by guanosine 5'-diphosphate inhibition of UCP1. NAD<sup>+</sup> cycling with NADH requires complex I electron flow and is needed to form OAA. Therefore, to assess the role of electron transit, we perturbed flow using a small molecule, N1-(3-acetamidophenyl)-N2-(2-(4-methyl-2-(p-tolyl)thiazol-5-yl)ethyl)oxalamide. We observed decreased OAA, increased NADH/NAD<sup>+</sup>, and increased succinate-supported mitochondrial respiration under conditions of low ΔΨ (IBAT) but not high ΔΨ (heart). In summary, complex II-energized respiration in IBAT mitochondria is tempered by complex I-derived OAA in a manner dependent on UCP1. These dynamics depend on electron transit in complex I.<br />
|keywords=S1QEL 1.1, Brown adipose tissue, Mitochondrial respiratory chain, Succinate dehydrogenase<br />
|editor=[[Plangger M]],<br />
|mipnetlab=US IA Iowa City Sivitz WI<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|organism=Mouse<br />
|tissues=Heart, Skeletal muscle, Fat<br />
|preparations=Isolated mitochondria<br />
|enzymes=Uncoupling protein<br />
|topics=ADP, mt-Membrane potential<br />
|couplingstates=OXPHOS<br />
|pathways=N, S<br />
|instruments=Oxygraph-2k, TPP<br />
|additional=2019-08,<br />
}}</div>
Krumschnabel Gerhard
https://wiki.oroboros.at/index.php?title=Ramalho_2019_J_Leukoc_Biol&diff=184225
Ramalho 2019 J Leukoc Biol
2019-08-09T08:30:21Z
<p>Krumschnabel Gerhard: </p>
<hr />
<div>{{Publication<br />
|title=Ramalho T, Ramalingam L, Filgueiras L, Festuccia W, Jancar S, Moustaid-Moussa N (2019) Leukotriene-B4 modulates macrophage metabolism and fat loss in type 1 diabetic mice. J Leukoc Biol [Epub ahead of print].<br />
|info=[https://www.ncbi.nlm.nih.gov/pubmed/31242337 PMID: 31242337]<br />
|authors=Ramalho T, Ramalingam L, Filgueiras L, Festuccia W, Jancar S, Moustaid-Moussa N<br />
|year=2019<br />
|journal=J Leukoc Biol<br />
|abstract=Serum levels of leukotriene-B4 (LTB4) are increased in type 1 diabetes (T1D) and it mediates systemic inflammation and macrophage reprogramming associated with this condition. Herein, we investigated the involvement of LTB4 in adiposity loss, hyperlipidemia, and changes in macrophage metabolism in a mouse model of streptozotocin-induced T1D. LTB4 receptor (BLT1) antagonist u75302 was employed to block LTB4 effects. As expected, hypoinsulinemia in T1D was associated with hyperglycemia, low levels of glucagon, hyperlipidemia, significant body fat loss, and increased white adipose tissue expression of Fgf21, a marker for lipolysis. With the exception of hyperglycemia and hypoglucagonemia, blockade of LTB4 signaling reverted these parameters in T1D mice. Along with hyperlipidemia, macrophages from T1D mice exhibited higher lipid uptake and accumulation. These cells also had enhanced glycolysis and oxidative metabolism and these parameters were dependent on the mitochondrial uncoupling respiration, as evidenced by elevated expression of oxidation markers carnitine palmitoyltransferase and uncoupling protein 1. Interestingly, all these parameters were at least partially reverted in T1D mice treated with u75302. Altogether, these findings suggest that in T1D mice LTB4/BLT1 is involved in the fat loss, hyperlipidemia, and increased macrophage lipid uptake and metabolism with an important involvement of mitochondrial uncoupling activity. These previously unrecognized LTB4/BLT1 functions may be explored in future to therapeutically alleviate severity of hyperlipidemia and systemic inflammation in T1D.<br />
<br />
<small>©2019 Society for Leukocyte Biology.</small><br />
|keywords=Energetic metabolism, Hyperlipidemia, Leukotriene-B4, Macrophage, Type 1 diabetes, Uncoupling cellular respiration<br />
|editor=[[Plangger M]],<br />
|mipnetlab=BR Sao Paulo Festuccia W<br />
}}<br />
{{Labeling<br />
|area=Respiration<br />
|diseases=Diabetes<br />
|organism=Mouse<br />
|tissues=Macrophage-derived<br />
|preparations=Intact cells<br />
|enzymes=Uncoupling protein<br />
|couplingstates=ROUTINE<br />
|pathways=ROX<br />
|instruments=Oxygraph-2k<br />
|additional=2019-08,<br />
}}</div>
Krumschnabel Gerhard