Difference between revisions of "Lemieux 2019b MiP2019"

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Altered mitochondrial metabolism in the diabetic heart.

Link: MiP2019

Makrecka-Kuka M, Liepinsh E, Murray AJ, Lemieux H, Dambrova M, Tepp K, Puurand M4 Kaambre T, Han WH, de Goede P, O’Brien KA, Turan B, Tuncay E, Olgar Y, Rolo AP, Palmeira CM, Boardman NT, Wuest RCI, Larsen TS (2019)

Event: MiP2019

Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from fatty acid-induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

• Bioblast editor: Plangger M, Tindle-Solomon L • O2k-Network Lab: CA Edmonton Lemieux H

Labels:

Organism: Other invertebrates

Affiliations

Makrecka-Kuka M(1), Liepinsh E(1), Murray AJ(2), Lemieux H(3), Dambrova M(1), Tepp K(4), Puurand M(4), Käämbre T(4), Han WH(5), de Goede P(6), O’Brien KA(2), Turan B(6), Tuncay E(7), Olgar Y(7), Rolo AP(8), Palmeira CM(8), Boardman NT(9), Wüst RCI(10), Larsen TS(9)

Latvian Institute of Organic Synthesis, Riga, Latvia
Department of Physiology, Development and Neuroscience, University of Cambridge, UK
Faculty Saint-Jean, Women and Children's Health Research Institute, Department of Medicine, University of Alberta, Canada
National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
Faculty Saint-Jean University of Alberta, Canada
Laboratory of Endocrinology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, Amsterdam, The Netherlands
Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
Department of Life Sciences, University of Coimbra and Center for Neurosciences and Cell Biology, University of Coimbra, Portugal
Cardiovascular Research Group, Department of Medical Biology, UiT the Arctic University of Norway
Laboratory for Myology, Faculty of Behavioural and Movement Sciences, Department of Human Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

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 {{Abstract
-|title=[[Image:LemieuxH.jpg|left|90px|Hélène Lemieux]] Partial prevention of oxidative stress damage to mitochondria with photobiomodulation.
+|title=[[Image:LemieuxH.jpg|left|90px|Hélène Lemieux]] Altered mitochondrial metabolism in the diabetic heart.
 |info=[[MiP2019]]
-|authors=Lemieux H, Han WH, Lessard M, Mast H, Anfray A, Holody C
+|authors=Makrecka-Kuka M, Liepinsh E, Murray AJ, Lemieux H, Dambrova M, Tepp K, Puurand M4 Kaambre T, Han WH, de Goede P, O’Brien KA, Turan B, Tuncay E, Olgar Y, Rolo AP, Palmeira CM, Boardman NT, Wuest RCI, Larsen TS
 |year=2019
 |event=MiP2019
 |abstract=[[Image:MITOEAGLE-logo.jpg|left|100px|link=http://www.mitoglobal.org/index.php/MITOEAGLE|COST Action MitoEAGLE]]
-Mitochondrial dysfunction is now recognized as an important factor in the pathogenesis of multiple diseases. In the past decades, photobiomodulation (PBM) has gained increasing interest as a potential mitochondria-targeting therapy. PBM involves the administration of a single or series of near-infrared (NIR) light exposures at low intensity. It has a great advantage of being a non-invasive treatment. Multiple beneficial effects of PBM have been reported in the literature which include a reduction in pain, inflammation, and edema, a regeneration of damaged tissues, a neuroprotective effect, an increase in toxin resistance and some anti-oxidative attributes [1, 2]. The currently accepted model proposes that functional changes in mitochondria have a strong involvement in the mechanism. While there has been a great amount of research on the clinical observations and biochemical pathway activations of PBM (i.e. secondary effects), the direct changes to mitochondria (i.e. primary effect) are not as well studied and remain somewhat controversial. Consequently, the present study is aimed at providing a more accurate understanding of the functional changes to mitochondria in response to NIR light exposure in normal conditions or as a protection against oxidative stress injuries.
+Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from fatty acid-induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.
-The planarian flatworm ''Dugesia Tigrina'' is used as the animal model [3]. It has the advantages of being small and translucent, offering the possibility to study the effects on the whole organism. In 6-well plates, the animals were either kept under normal conditions (control) or exposed to NIR light (78 s; 0.5 J/cm<sup>2</sup>). The light exposure did not alter the temperature of the plates, and was followed by one hour at room temperature. Then, some wells were exposed to oxidative stress using 10 mM hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) for 1 min. Mitochondrial function was measured using high-resolution respirometry (Oxygraph 2k; Oroboros Instruments Inc.). Four treatment groups were included: (1) control, without NIR and H<sub>2</sub>O<sub>2</sub>, (2) NIR without H<sub>2</sub>O<sub>2</sub> (3) H<sub>2</sub>O<sub>2</sub> without NIR, and (4) treated with both NIR and H<sub>2</sub>O<sub>2</sub>. The multiple substrate-inhibitor protocol allowed for the measurement of three states: LEAK respiration (before the addition of ADP), OXPHOS capacity (in the ADP-activated state, coupled oxidative phosphorylation) and ET capacity (electron transfer capacity after uncoupling). The capacities of different pathways and steps were included in the protocol, i.e., the NADH pathway (with NADH-linked substrates giving electrons into complex I), the Succinate pathway (with succinate providing electrons into complex II), the NS-pathway (with complex I- and II-linked substrates simultaneously), and the complex IV. Respiratory capacities were expressed in flux per mass or in flux control ratio (FCR), relative to the maximal ET-capacity. ANOVA’s with post-hoc Tukey tests were carried out and a p<0.05 was considered significant (N=22 per group).
-Exposure of the live planarian to 10 mM of H<sub>2</sub>O<sub>2</sub> causes changes in the mitochondrial respiratory capacity, especially a reduction in NADH pathway OXPHOS capacity (p˂0.001) and in the Succinate pathway ET-capacity (p=0.005), as well as a slight increase in LEAK respiration (p=0.010). The OXPHOS limitation by the phosphorylation system was also increased in the group treated with H<sub>2</sub>O<sub>2</sub> compared to the control (p˂0.001). This suggests that there is an effect produced by H<sub>2</sub>O<sub>2</sub> exposure on component(s) of the phosphorylation system. In contrast, the hydrogen peroxide treatment had no effect on complex IV capacity. Without exposure to hydrogen peroxide, PBM did not affect significantly any of the mitochondrial parameters measured. PMB therapy applied to the planarian previous to H<sub>2</sub>O<sub>2</sub> exposure successfully restored the Succinate pathway capacity to the level of the control. Furthermore, treatment with NIR decreases the sensitivity of the mitochondrial outer membrane to damage when exposed to H<sub>2</sub>O<sub>2</sub> (p=0.026), even if the membrane sensitivity was not affected by H<sub>2</sub>O<sub>2</sub> exposure alone (p=0.835). In contrast, the NADH-pathway relative capacity and the limitation of OXPHOS by the phosphorylation system remained compromised by H<sub>2</sub>O<sub>2</sub> treatment even with pre-exposure to PBM.
-Our study points toward a potential new targets of PBM therapy on mitochondrial function, including the complex II and outer mitochondrial membrane fragility. More studies are needed to increase our knowledge of the function of PBM treatment in rescuing damaged mitochondria under various conditions, and to reach a better understanding of the mechanism of this promising therapy.
 |editor=[[Plangger M]], [[Tindle-Solomon L]]
 |mipnetlab=CA Edmonton Lemieux H
 }}
 {{Labeling
-|area=Respiration, mt-Medicine
-|injuries=Oxidative stress;RONS
 |organism=Other invertebrates
-|couplingstates=LEAK, OXPHOS, ET
-|pathways=N, S, CIV, NS
-|instruments=Oxygraph-2k
 }}
 == Affiliations ==
-::::Lemieux H(1,2,3), Han WH(1), Lessard M(1), Mast H(1), Anfray A(1), Holody C(1,2)
+::::Makrecka-Kuka M(1), Liepinsh E(1), Murray AJ(2), Lemieux H(3), Dambrova M(1), Tepp K(4), Puurand M(4), Käämbre T(4), Han WH(5), de Goede P(6), O’Brien KA(2), Turan B(6), Tuncay E(7), Olgar Y(7), Rolo AP(8), Palmeira CM(8), Boardman NT(9), Wüst RCI(10), Larsen TS(9)
-::::#Fac Saint-Jean,
-::::#Women and Children’s Health Research Inst (WCHRI),
-::::#Dept Medicine, Univ Alberta. - [email protected]
-== References ==
+::::#Latvian Institute of Organic Synthesis, Riga, Latvia
-::::#Hamblin MR (2018) Mechanisms and mitochondrial redox signaling in photobiomodulation. Photochem Photobiol 94:199-212.
+::::#Department of Physiology, Development and Neuroscience, University of Cambridge, UK
-::::#Hennessy M, Hamblin MR (2017) Photobiomodulation and the brain: a new paradigm. J Opt 19:013003.
+::::#Faculty Saint-Jean, Women and Children's Health Research Institute, Department of Medicine, University of Alberta, Canada
-::::#Lemieux H, Warren B (2012) An animal model to study human muscular diseases involving mitochondrial oxidative phosphorylation. J Bioenerg Biomembr 44:503-12.
+::::#National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
+::::#Faculty Saint-Jean University of Alberta, Canada
+::::#Laboratory of Endocrinology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, Amsterdam, The Netherlands
+::::#Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
+::::#Department of Life Sciences, University of Coimbra and Center for Neurosciences and Cell Biology, University of Coimbra, Portugal
+::::#Cardiovascular Research Group, Department of Medical Biology, UiT the Arctic University of Norway
+::::#Laboratory for Myology, Faculty of Behavioural and Movement Sciences, Department of Human Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.