Difference between revisions of "Juhasz 2017 MiPschool Obergurgl"
(Created page with "{{Abstract |title=left|60px|link=http://www.mitoglobal.org/index.php/MITOEAGLE|COST Action MITOEAGLE |info=MITOEAGLE |year=2017 |even...") Â |
|||
Line 1: | Line 1: | ||
{{Abstract | {{Abstract | ||
|title=[[File:MITOEAGLE-representation.jpg|left|60px|link=http://www.mitoglobal.org/index.php/MITOEAGLE|COST Action MITOEAGLE]] | |title=[[File:MITOEAGLE-representation.jpg|left|60px|link=http://www.mitoglobal.org/index.php/MITOEAGLE|COST Action MITOEAGLE]] | ||
Blockade of N-methyl-D-aspartate receptors improves polymicrobial sepsis-evoked mitochondrial dysfunction in rats. | |||
|info=[[MITOEAGLE]] | |info=[[MITOEAGLE]] | ||
|authors=Juhasz L, Poles MZ, Tallosy SZP, Rutai A, Boros M, Vecsei L, Szabo A, Kaszaki J | |||
|year=2017 | |year=2017 | ||
|event=MiPschool Obergurgl 2017 | |event=MiPschool Obergurgl 2017 | ||
|abstract=[[Image:MITOEAGLE-logo.jpg|left|100px|link=http://www.mitoglobal.org/index.php/MITOEAGLE|COST Action MITOEAGLE]] | |abstract=[[Image:MITOEAGLE-logo.jpg|left|100px|link=http://www.mitoglobal.org/index.php/MITOEAGLE|COST Action MITOEAGLE]] | ||
Sepsis-related changes in oxygen dynamics and subsequent multi-organ failure are associated with mitochondrial dysfunction and depleted energy supplies [1]. Recently, N-methyl-D-aspartate receptor (NMDA-R)-mediated increase in intracellular calcium (Ca<sup>2+</sup>) level has been suggested as a major source for mitochondrial Ca<sup>2+</sup> uptake and Ca<sup>2+</sup> overload [2,3]. However, the relationship between NMDA-Râlinked Ca<sup>2+</sup> entry and electron transport system function is still not fully elucidated. Thus, our main goal was to investigate whether NMDA-receptor antagonists, the natural kynurenic acid (KYNA) and its synthetic analogue, SZR-72 affects mitochondrial respiration in a rodent model of peritonitis-induced sepsis (PS). | |||
PS was induced in male Sprague Dawley rats by intraperitoneal injection of faeces (n=18, 0.6 g/kg body weight). Animals in control group were given saline only (C; n=6). NMDA-R was blocked by by either KYNA or SZR-72 (160 ”mol/kg, ip. administered twice ip. 3h and 22 h after PS induction). Blood gases and haemodynamic parameters were monitored under anaesthesia and then animals were sacrificed for the assessment of cellular respiratory function. Mitochondrial Complex-I dependent (CI; glutamate/malate+ADP) and Complex-II dependent (CII; rotenone+succinate+ADP) mitochondrial oxygen consumption was assessed from liver homogenates using high-resolution respirometry (O2k, OROBOROS Instruments, Innsbruck, Austria). | |||
We found that glutamate/malate supported LEAK respiration and succinate supported LEAK respiration decreased markedly 24 h after the induction of PS. Similarly, both CI and CII-driven OXPHOS exhibited significantly lower values in septic rats, compared to sham-operated control animals (40% and 35%, respectively). However, the PS-induced decrease in CII-linked substrate oxidation and CII-linked OXPHOS capacity were markedly restored either by KYNA (72%) or SZR-72 (90%) while CI-linked mitochondrial respiratory function was only affected by SZR-72 administration. In addition, electron transport coupled to ATP synthesis evaluated by respiratory control ratio, observed to be higher in SZR-72 treated rats (RCR: 30%). | |||
Our hypothesis suggests that inhibition of NMDA receptors, perhaps through the regulation of intramitochondrial Ca<sup>2+</sup> pool and/or by attenuating the overproduction of reactive oxygen species, may modulate mitochondrial respiration and improve ADP utilisation to produce ATP. | |||
|editor=[[Kandolf G]], | |||
}} | |||
{{Labeling | |||
|area=Respiration | |||
|diseases=Other | |||
|organism=Rat | |||
|tissues=Liver | |||
|preparations=Homogenate | |||
|topics=Calcium | |||
|couplingstates=LEAK, OXPHOS | |||
|pathways=N, S | |||
|instruments=Oxygraph-2k | |||
}} | }} | ||
== Affiliations == | == Affiliations == | ||
:::: (1) | :::: JuhĂĄsz L(1), Poles MZ(1), TallĂłsy SZP(1), Rutai A(1), Boros M(1), VĂ©csei L(2), SzabĂł A(1), Kaszaki J(1) | ||
 | |||
::::#Univ Szeged, Inst Surgical Research | |||
::::#Univ Szeged, Dept Neurol.- [email protected] | |||
 | |||
== References and support == | |||
::::#Singer M (2014) The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 5:66-72. | |||
::::#Duan Y, Gross RA, Sheu SS (2007) Ca<sup>2+</sup>-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity. J Physiol 585:741-58. | |||
::::#Pinto BB, Dyson A, Umbrello M, Carré JE, Ritter C, Clatworthy I, Duchen MR, Singer M (2017) Improved Survival in a long term-model of sepsis is associated with reduced mitochondrial calcium uptake despite increased energetic demand. Crit Care Med [Epub ahead of print] | |||
 | |||
:::: | ::::Financial support: NKFIH K116689, GINOP-2.3.2-15-2016-00034 | ||
Revision as of 11:28, 9 June 2017
Blockade of N-methyl-D-aspartate receptors improves polymicrobial sepsis-evoked mitochondrial dysfunction in rats. |
Link: MITOEAGLE
Juhasz L, Poles MZ, Tallosy SZP, Rutai A, Boros M, Vecsei L, Szabo A, Kaszaki J (2017)
Event: MiPschool Obergurgl 2017
Sepsis-related changes in oxygen dynamics and subsequent multi-organ failure are associated with mitochondrial dysfunction and depleted energy supplies [1]. Recently, N-methyl-D-aspartate receptor (NMDA-R)-mediated increase in intracellular calcium (Ca2+) level has been suggested as a major source for mitochondrial Ca2+ uptake and Ca2+ overload [2,3]. However, the relationship between NMDA-Râlinked Ca2+ entry and electron transport system function is still not fully elucidated. Thus, our main goal was to investigate whether NMDA-receptor antagonists, the natural kynurenic acid (KYNA) and its synthetic analogue, SZR-72 affects mitochondrial respiration in a rodent model of peritonitis-induced sepsis (PS).
PS was induced in male Sprague Dawley rats by intraperitoneal injection of faeces (n=18, 0.6 g/kg body weight). Animals in control group were given saline only (C; n=6). NMDA-R was blocked by by either KYNA or SZR-72 (160 ”mol/kg, ip. administered twice ip. 3h and 22 h after PS induction). Blood gases and haemodynamic parameters were monitored under anaesthesia and then animals were sacrificed for the assessment of cellular respiratory function. Mitochondrial Complex-I dependent (CI; glutamate/malate+ADP) and Complex-II dependent (CII; rotenone+succinate+ADP) mitochondrial oxygen consumption was assessed from liver homogenates using high-resolution respirometry (O2k, OROBOROS Instruments, Innsbruck, Austria).
We found that glutamate/malate supported LEAK respiration and succinate supported LEAK respiration decreased markedly 24 h after the induction of PS. Similarly, both CI and CII-driven OXPHOS exhibited significantly lower values in septic rats, compared to sham-operated control animals (40% and 35%, respectively). However, the PS-induced decrease in CII-linked substrate oxidation and CII-linked OXPHOS capacity were markedly restored either by KYNA (72%) or SZR-72 (90%) while CI-linked mitochondrial respiratory function was only affected by SZR-72 administration. In addition, electron transport coupled to ATP synthesis evaluated by respiratory control ratio, observed to be higher in SZR-72 treated rats (RCR: 30%).
Our hypothesis suggests that inhibition of NMDA receptors, perhaps through the regulation of intramitochondrial Ca2+ pool and/or by attenuating the overproduction of reactive oxygen species, may modulate mitochondrial respiration and improve ADP utilisation to produce ATP.
âą Bioblast editor: Kandolf G
Labels: MiParea: Respiration Pathology: Other
Organism: Rat Tissue;cell: Liver Preparation: Homogenate
Regulation: Calcium Coupling state: LEAK, OXPHOS Pathway: N, S HRR: Oxygraph-2k
Affiliations
- JuhĂĄsz L(1), Poles MZ(1), TallĂłsy SZP(1), Rutai A(1), Boros M(1), VĂ©csei L(2), SzabĂł A(1), Kaszaki J(1)
- Univ Szeged, Inst Surgical Research
- Univ Szeged, Dept Neurol.- [email protected]
References and support
- Singer M (2014) The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 5:66-72.
- Duan Y, Gross RA, Sheu SS (2007) Ca2+-dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity. J Physiol 585:741-58.
- Pinto BB, Dyson A, Umbrello M, Carré JE, Ritter C, Clatworthy I, Duchen MR, Singer M (2017) Improved Survival in a long term-model of sepsis is associated with reduced mitochondrial calcium uptake despite increased energetic demand. Crit Care Med [Epub ahead of print]
- Financial support: NKFIH K116689, GINOP-2.3.2-15-2016-00034
Instructions
- All details: Abstracts