Succinate dehydrogenase inhibition with malonate during reperfusion reduces infarct size by preventing mitochondrial permeability transition

Valls-Lacalle, Laura; Barba, Ignasi; Miró-Casas, Elisabet; Alburquerque-Béjar, Juan J.; Ruiz‐Meana, Marisol; Fuertes-Agudo, Marina; Rodríguez‐Sinovas, Antonio; Garcı́a-Dorado, David

doi:10.1093/cvr/cvv279

Cited by 127 publications

(134 citation statements)

References 41 publications

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“…9). This scenario is consistent with recent experimental findings that SDH inhibition with malonate at the start of reperfusion inhibits both ROS production and PTP opening/cell damage (45). It is also consistent with the observation that the complex I inhibitor rotenone protects against I/R injury by suppressing RET and inhibiting the initial PTP opening that activates succinate-driven ROS production by complexes II and III.…”

Section: Relevance To I/r Injurysupporting

confidence: 92%

Reactive oxygen species production induced by pore opening in cardiac mitochondria: The role of complex II

Kôrge

John

Calmettes

et al. 2017

Journal of Biological Chemistry

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Succinate-driven reverse electron transport (RET) through complex I is hypothesized to be a major source of reactive oxygen species (ROS) that induces permeability transition pore (PTP) opening and damages the heart during ischemia/reperfusion. Because RET can only generate ROS when mitochondria are fully polarized, this mechanism is self-limiting once PTP opens during reperfusion. In the accompanying article (Korge, P., Calmettes, G., John, S. A., and Weiss, J. N. (2017) 292, 9882-9895), we showed that ROS production after PTP opening can be sustained when complex III is damaged (simulated by antimycin). Here we show that complex II can also contribute to sustained ROS production in isolated rabbit cardiac mitochondria following inner membrane pore formation induced by either alamethicin or calcium-induced PTP opening. Two conditions are required to maximize malonate-sensitive ROS production by complex II in isolated mitochondria: () complex II inhibition by atpenin A5 or complex III inhibition by stigmatellin that results in succinate-dependent reduction of the dicarboxylate-binding site of complex II (site II); () pore opening in the inner membrane resulting in rapid efflux of succinate/fumarate and other dicarboxylates capable of competitively binding to site II The decrease in matrix [dicarboxylate] allows O access to reduced site II, thereby making electron donation to O possible, explaining the rapid increase in ROS production provided that site II is reduced. Because ischemia is known to inhibit complexes II and III and increase matrix succinate/fumarate levels, we hypothesize that by allowing dicarboxylate efflux from the matrix, PTP opening during reperfusion may activate sustained ROS production by this mechanism after RET-driven ROS production has ceased.

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Section: Relevance To I/r Injurysupporting

confidence: 92%

Reactive oxygen species production induced by pore opening in cardiac mitochondria: The role of complex II

Kôrge

John

Calmettes

et al. 2017

Journal of Biological Chemistry

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“…19 Calpain activation occurring upon normalization of intracellular pH in cells with Ca 2+ has been demonstrated to contribute to cardiomyocyte death. 20 Reactive oxygen species may induce MPTP opening, and interventions attenuating mitochondrial ROS production can prevent MPTP opening and reduce MI size, 21 but they also have extra-mitochondrial targets, the importance of which needs to be clarified. A potentially important target of ROS is the tetrahydrobiopterin–eNOS complex, which may be dissociated by oxidation, resulting in peroxynitrite formation and reduced NO availability.…”

Section: Why Has It Been So Difficult To Prevent Myocardial Reperfusimentioning

confidence: 99%

Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations

et al. 2016

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“…Indeed, recent work in the isolated mouse heart has demonstrated that the administration of malonate during the first 15 minutes of reperfusion was cardioprotective only through the inhibition of succinate reoxidation and the reduction in ROS production and mPTP opening. 98 Whether this important result can be translated to in vivo models, however, remains to be determined.…”

Section: Pharmacological Inhibitors Of the Respiratory Chain As Theramentioning

confidence: 99%

Moving Forwards by Blocking Back-Flow

Pell

Chouchani

Murphy

et al. 2016

Circulation Research

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Mitochondrial reactive oxygen species production has emerged as an important pathological mechanism in myocardial ischemia/reperfusion injury. Attempts at targeting reactive oxygen species by scavenging using antioxidants have, however, been clinically disappointing. This review will provide an overview of the current understanding of mitochondrial reactive oxygen species in ischemia/reperfusion injury. We will outline novel therapeutic approaches designed to directly target the mitochondrial respiratory chain and prevent excessive reactive oxygen species production and its associated pathology. This approach could lead to more effective interventions in an area where there is an urgent need for new treatments.

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Succinate dehydrogenase inhibition with malonate during reperfusion reduces infarct size by preventing mitochondrial permeability transition

Abstract: Succinate dehydrogenase inhibition with malonate at the onset of reperfusion reduces infarct size in isolated mice hearts through reduction in ROS production and mitochondrial permeability transition pore opening.

Cited by 127 publications

References 41 publications

Reactive oxygen species production induced by pore opening in cardiac mitochondria: The role of complex II

Reactive oxygen species production induced by pore opening in cardiac mitochondria: The role of complex II

Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations

Moving Forwards by Blocking Back-Flow

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