Global ischaemia induces a biphasic response of the mitochondrial respiratory chain. Anoxic pre-perfusion protects against ischaemic damage

Veitch, Keith; Hombroeckx, Annick; Caucheteux, Danielle; Pouleur, H.; Hue, Louis

doi:10.1042/bj2810709

Cited by 143 publications

(100 citation statements)

References 33 publications

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“…Complex 1 and 5 have been identified as the two more fragile mitochondrial respiratrypan blue exclusion test. Taken together, our results indicate that LDH and MTT tests do not adequately astory chain complexes (11,19,31,32,43). Indeed, the activity of complex 1 is rapidly altered following cold issess viability and that intracellular ATP concentration is probably the most sensitive parameter to detect early chemia of whole organs (19,31), by a still unknown mechanism.…”

Section: Activation Dna Fragmentation and Apoptosismentioning

confidence: 91%

Cryopreservation of Human Hepatocytes Alters the Mitochondrial Respiratory Chain Complex 1

et al. 2007

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Transplantation of human hepatocytes has recently been demonstrated as a safe alternative to partially correct liver inborn errors of metabolism. Cryopreservation remains the most appropriate way of cell banking. However, mitochondrial-mediated apoptosis has been reported after cryopreservation and little is known on the involved molecular mechanisms. The aim of this study was to investigate mitochondrial functions of freshly isolated and cryopreserved/thawed hepatocytes from mice and humans. We report here that cryopreservation induced a dramatic drop of ATP levels in hepatocytes. The oxygen consumption rate of cryopreserved/ thawed hepatocytes was significantly lower compared to fresh cells. In addition, the uncoupling effect of 2,4-dinitrophenol was lost, in parallel with a reduction of mitochondrial membrane potential. Furthermore, a decrease in mitochondrial respiratory rate was evidenced on permeabilized hepatocytes in the presence of substrate for the respiratory chain complex 1. Interestingly, this effect was less marked with a substrate for complex 2. Electron microscopy examination indicated that mitochondria were swollen and devoid of cristae after cryopreservation. These changes could explain the cytosolic release of the proapoptotic protein cytochrome c in cryopreserved cells. Nevertheless, no caspase 9-3 activation and only few apoptotic and necrotic cells were found, indicating that the subsequent cell death program was not yet evidenced. Our results demonstrate that cryopreservation of hepatocytes induced alteration of the mitochondrial machinery. They also suggest that, in addition to technical progress in the cryopreservation procedure, protection of the respiratory chain complex 1 should be considered to improve the quality of cryopreserved hepatocytes.

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Section: Activation Dna Fragmentation and Apoptosismentioning

confidence: 91%

Cryopreservation of Human Hepatocytes Alters the Mitochondrial Respiratory Chain Complex 1

et al. 2007

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“…Oxidative phosphorylation is inhibited during hypoxia and deteriorates upon reoxygenation. 27,40 The progressive deterioration of mitochondrial function during reperfusion may result from MPT triggered by the normalization of intracellular pH and burst of ROS activity. 41 Opening of the MPT pore would cause immediate collapse of the mitochondrial membrane potential and inhibits ATP synthesis.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-Targeted Peptide Accelerates ATP Recovery and Reduces Ischemic Kidney Injury

Szeto

Liu

Soong

et al. 2011

Journal of the American Society of Nephrology

260

244

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The burst of reactive oxygen species (ROS) during reperfusion of ischemic tissues can trigger the opening of the mitochondrial permeability transition (MPT) pore, resulting in mitochondrial depolarization, decreased ATP synthesis, and increased ROS production. Rapid recovery of ATP upon reperfusion is essential for survival of tubular cells, and inhibition of oxidative damage can limit inflammation. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge mitochondrial ROS and inhibit MPT, suggesting that it may protect against ischemic renal injury. Here, in a rat model of ischemia-reperfusion (IR) injury, treatment with SS-31 protected mitochondrial structure and respiration during early reperfusion, accelerated recovery of ATP, reduced apoptosis and necrosis of tubular cells, and abrogated tubular dysfunction. In addition, SS-31 reduced medullary vascular congestion, decreased IR-mediated oxidative stress and the inflammatory response, and accelerated the proliferation of surviving tubular cells as early as 1 day after reperfusion. In summary, these results support MPT as an upstream target for pharmacologic intervention in IR injury and support early protection of mitochondrial function as a therapeutic maneuver to prevent tubular apoptosis and necrosis, reduce oxidative stress, and reduce inflammation. SS-31 holds promise for the prevention and treatment of acute kidney injury. Acute kidney injury (AKI) develops in 5% of hospitalized patients and is associated with significant morbidity. Ischemia is the most common cause of AKI. Despite our current knowledge of the pathophysiology underlying renal ischemia-reperfusion (IR) injury, pharmacologic interventions have not reduced the mortality and morbidity associated with AKI.Rapid recovery of ATP after ischemia is essential for cell survival after IR injury. A profound reduction in intracellular ATP occurs early after onset of ischemia and leads to cytoskeletal derangements, membrane alterations, and cell death by apoptosis and necrosis. 1 Disruption of the cytoskeleton leads to redistribution of integrins and Na ϩ ,K ϩ -ATPase from the basal membrane, resulting in detachment of viable cells from the basement membrane and impairment of Na ϩ reabsorption. The mode of cell death depends on the duration of ischemia and the region of the nephron. Cell death is usually restricted to the outer medullary region where oxygen tension drops precipitously at the corticomedullary junction. 2 The proximal tubules are particularly susceptible to IR injury because they have minimal glycolytic capacity and must rely on mitochondrial metabolism for ATP synthesis. [3][4][5] Ischemia causes damage to all components of the mitochondrial electron transport chain (ETC), resulting in decreased oxidative phosphorylation upon reperfusion. 6 In addition, mitochondria are the primary source of reactive oxygen species (ROS). 6,7 Mitochondria can undergo further damage upon reperfusion because of mitochondrial permeability transition (MPT). During ischemia, elevated mitocho...

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“…This effect of trimetazidine was attributed by the authors not to its antioxidant properties, but to changes in lipid metabolism (Fantini et al, 1994). In other models of ischemia-reperfusion, it has been demonstrated that the impact of ischemia on the mitochondrial respiratory chain mainly occurs at the level of complex I (Veitch et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia

Monteiro

Duarte²,

Gonçalves

et al. 2004

European Journal of Pharmacology

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Trimetazidine is an anti-ischemic drug whose cytoprotective mechanisms are not yet fully understood (but until now mainly related to the trimetazidine-induced bmetabolic shiftQ from lipid h-oxidation to glucose aerobic oxidation). We studied the effect of trimetazidine on the mitochondrial function of ischemic Wistar rat hearts perfused with glucose, using a model of ex-vivo perfusion (Langendorff system). We measured the electrical potential of the mitochondrial membrane, O 2 consumption by the respiratory chain, energy charges generated and the enzyme activities of the respiratory chain complexes. In this model, trimetazidine had a preferential action on the oxidative system (mainly on complex I), increasing its enzyme activity and decreasing O 2 consumption after phosphorylation; this could decrease oxygen free radical production and increase mitochondrial integrity, thus allowing the maintenance of the electrical potential. These results allow us to better understand the cytoprotective effects of trimetazidine in coronary artery disease. D

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Global ischaemia induces a biphasic response of the mitochondrial respiratory chain. Anoxic pre-perfusion protects against ischaemic damage

Cited by 143 publications

References 33 publications

Cryopreservation of Human Hepatocytes Alters the Mitochondrial Respiratory Chain Complex 1

Cryopreservation of Human Hepatocytes Alters the Mitochondrial Respiratory Chain Complex 1

Mitochondria-Targeted Peptide Accelerates ATP Recovery and Reduces Ischemic Kidney Injury

Protective effect of trimetazidine on myocardial mitochondrial function in an ex-vivo model of global myocardial ischemia

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