BBA - Molecular Cell Research (v.1813, #7)

Preface to Mitochondria and Cardioprotection by Fabio Di Lisa; Rainer Schulz; Elizabeth Murphy (1261-1262).

Hypoxia-inducible factor 1 (HIF-1) mediates adaptive responses to reduced oxygen availability by regulating gene expression. A critical cell-autonomous adaptive response to chronic hypoxia controlled by HIF-1 is reduced mitochondrial mass and/or metabolism. Exposure of HIF-1-deficient fibroblasts to chronic hypoxia results in cell death due to excessive levels of reactive oxygen species (ROS). HIF-1 reduces ROS production under hypoxic conditions by multiple mechanisms including: a subunit switch in cytochrome c oxidase from the COX4-1 to COX4-2 regulatory subunit that increases the efficiency of complex IV; induction of pyruvate dehydrogenase kinase 1, which shunts pyruvate away from the mitochondria; induction of BNIP3, which triggers mitochondrial selective autophagy; and induction of microRNA-210, which blocks assembly of Fe/S clusters that are required for oxidative phosphorylation. HIF-1 is also required for ischemic preconditioning and this effect may be due in part to its induction of CD73, the enzyme that produces adenosine. HIF-1-dependent regulation of mitochondrial metabolism may also contribute to the protective effects of ischemic preconditioning. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► Hypoxia-inducible factor 1 (HIF-1) maintains oxygen homeostasis by directly activating transcription of target genes and by indirectly repressing gene expression through the transactivation of genes encoding transcriptional repressors and microRNAs. ► Within each cell, O2 supply and utilization must be optimized in order to prevent the production of excess reactive oxygen species, which can cause oxidative damage to cellular DNA, proteins, and lipids. HIF-1 regulates the balance between oxidative and glycolytic metabolism by directly activating transcription of target genes encoding lactate dehydrogenase A, pyruvate dehydrogenase kinase 1, BNIP3, cytochrome c oxidase subunit 4-2, mitochondrial protease LON, and microRNA miR-210. ► HIF-1 is a critical mediator of hypoxic and ischemic cardiac preconditioning. Further studies are required to determine whether regulation of myocardial metabolism plays a key role in preconditioning.
Keywords: Electron transport chain; Heart; Myocardial; Oxygen; Reactive oxygen species; Respiration;

The PGC-1 family of regulated coactivators, consisting of PGC-1α, PGC-1β and PRC, plays a central role in a regulatory network governing the transcriptional control of mitochondrial biogenesis and respiratory function. These coactivators target multiple transcription factors including NRF-1, NRF-2 and the orphan nuclear hormone receptor, ERRα, among others. In addition, they themselves are the targets of coactivator and co-repressor complexes that regulate gene expression through chromatin remodeling. The expression of PGC-1 family members is modulated by extracellular signals controlling metabolism, differentiation or cell growth and in some cases their activities are known to be regulated by post-translational modification by the energy sensors, AMPK and SIRT1. Recent gene knockout and silencing studies of many members of the PGC-1 network have revealed phenotypes of wide ranging severity suggestive of complex compensatory interactions or broadly integrative functions that are not exclusive to mitochondrial biogenesis. The results point to a central role for the PGC-1 family in integrating mitochondrial biogenesis and energy production with many diverse cellular functions. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► Respiratory chain expression requires nuclear and mitochondrial regulatory factors. ► Essential and nonessential nuclear factors contribute to respiratory chain expression. ► PGC-1α and β are important regulators of tissue-specific metabolic function. ► PRC is a growth-regulated member of the PGC-1 coactivator family. ► PRC silencing leads to a respiratory chain defect and abundant, abnormal mitochondria.
Keywords: Mitochondria; Respiration; Gene expression; Regulation; Transcription; Coactivator;

Caloric excess has been postulated to disrupt cardiac function via (i) the generation of toxic intermediates, (ii) via protein glycosylation and (iii) through the generation of reactive oxygen species. It is now increasingly being recognized that the nutrient intermediates themselves may modulate metabolic pathways through the post-translational modifications of metabolic enzymes. In light of the high energy demand of the heart, these nutrient mediated modulations in metabolic pathway functioning may play an important role in cardiac function and in the capacity of the heart to adapt to biomechanical stressors. In this review the role of protein acetylation and deacetylation in the control of metabolic programs is explored. Although not extensively investigated directly in the heart, the emerging data support that these nutrient mediated post-translational regulatory events (i) modulate cardiac metabolic pathways, (ii) integrate nutrient flux mediated post-translational effects with cardiac function and (iii) may be important in the development of cardiac pathology. Areas of investigation that need to be explored are highlighted. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► Caloric excess predisposes to altered cardiac energetics and function. ► Caloric excess similarly disrupts cardiac mitochondrial function. ► Acetylation of mitochondrial proteins may contribute to these nutrient effects. ► Sirtuin enzymes appear to directly modulate these processes in the mitochondria. ► Modulation of sirtuin biology may have beneficial cardiac effects.
Keywords: Sirtuins; Acetyltransferase; NAD+; Acetyl-CoA; Cardiac contraction; Cardiac hypertrophy;

Nuclear-encoded mitochondrial proteins and their role in cardioprotection by Kerstin Boengler; Gerd Heusch; Rainer Schulz (1286-1294).
During myocardial ischemia/reperfusion, mitochondria are both a source and a target of injury. In cardioprotective maneuvers such as ischemic and pharmacological pre- and postconditioning mitochondria have a decisive role. Since about 99% of the mitochondrial proteins are encoded in the nucleus, deleterious and protective mitochondrial effects most likely comprise the import of cytosolic proteins. The present review therefore discusses the role of mitochondria in myocardial ischemia/reperfusion injury and protection from it, focusing on some cytosolic proteins, which are translocated into mitochondria before, during, or following ischemia/reperfusion. Both morphological and functional alterations are discussed at the level of the heart, the cardiomyocyte and/or the mitochondrion itself. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► Mitochondria are both source and target of myocardial ischemia/reperfusion injury. ► Nuclear-encoded proteins are imported into mitochondria. ► Nuclear-encoded proteins affect mitochondrial morphology and function.
Keywords: Mitochondria; Ischemia/reperfusion; Cardioprotection; Import; Connexin 43; Protein kinases;

Mitochondrial turnover in the heart by Roberta A. Gottlieb; Åsa B. Gustafsson (1295-1301).
Mitochondrial quality control is increasingly recognized as an essential element in maintaining optimally functioning tissues. Mitochondrial quality control depends upon a balance between biogenesis and autophagic destruction. Mitochondrial dynamics (fusion and fission) allows for the redistribution of mitochondrial components. We speculate that this permits sorting of highly functional components into one end of a mitochondrion, while damaged components are segregated at the other end, to be jettisoned by asymmetric fission followed by selective mitophagy. Ischemic preconditioning requires autophagy/mitophagy, resulting in selective elimination of damaged mitochondria, leaving behind a population of robust mitochondria with a higher threshold for opening of the mitochondrial permeability transition pore. In this review we will consider the factors that regulate mitochondrial biogenesis and destruction, the machinery involved in both processes, and the biomedical consequences associated with altered mitochondrial turnover. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.►Mitochondrial quality control is accomplished by balanced destruction and production. ►Fission and fusion are essential for mitochondrial quality control. ►Mitophagy is mediated by Bnip3, Nix, Parkin, PINK1, and p62/SQSTM1. ►Impaired mitochondrial dynamics results in human disease. ►Mitophagy enables cardioprotection and metabolic reprogramming.
Keywords: Mitochondria; Mitophagy; Autophagy; Mitochondrial turnover; Cardioprotection;

What makes the mitochondria a killer? Can we condition them to be less destructive? by Elizabeth Murphy; Charles Steenbergen (1302-1308).
Cardioprotection, such as preconditioning and postconditioning, has been shown to result in a significant reduction in cell death. Many of the signaling pathways activated by cardioprotection have been elucidated, but there is still a lack of understanding of the mechanisms by which these signaling pathways reduce cell death. Mitochondria have been reported to be an important player in many types of apoptotic and necrotic cell death. If mitochondria play an important role in cell death, then it seems reasonable to consider that cardioprotective mechanisms might act, at least in part, by opposing mitochondrial cell death pathways. One of the major mechanisms of cell death in ischemia–reperfusion is suggested to be the opening of a large conductance pore in the inner mitochondrial membrane, known as the mitochondrial permeability transition pore. Inhibition of this mitochondrial pore appears to be one of the major mechanisms by which cardioprotection reduces cell death. Cardioprotection activates a number of signaling pathways that reduce the level of triggers (reactive oxygen species and calcium) or enhances inhibitors of the mitochondrial permeability transition pore at the start of reperfusion. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► The mitochondrial permeability transition pore (MPTP) opens during reperfusion. ► Opening of the MPTP is an important mediator of cell death in ischemia-reperfusion. ► Cardioprotection reduces activators of the MPTP such as Ca and ROS.
Keywords: Mitochondria; Nitric oxide; Phosphorylation; Calcium; Reactive oxygen species; Cardioprotection;

Redox regulation of the mitochondrial KATP channel in cardioprotection by Bruno B. Queliconi; Andrew P. Wojtovich; Sergiy M. Nadtochiy; Alicia J. Kowaltowski; Paul S. Brookes (1309-1315).
The mitochondrial ATP-sensitive potassium channel (mKATP) is important in the protective mechanism of ischemic preconditioning (IPC). The channel is reportedly sensitive to reactive oxygen and nitrogen species, and the aim of this study was to compare such species in parallel, to build a more comprehensive picture of mKATP regulation. mKATP activity was measured by both osmotic swelling and Tl+ flux assays, in isolated rat heart mitochondria. An isolated adult rat cardiomyocyte model of ischemia–reperfusion (IR) injury was also used to determine the role of mKATP in cardioprotection by nitroxyl. Key findings were as follows: (i) mKATP was activated by O2 and H2O2 but not other peroxides. (ii) mKATP was inhibited by NADPH. (iii) mKATP was activated by S-nitrosothiols, nitroxyl, and nitrolinoleate. The latter two species also inhibited mitochondrial complex II. (iv) Nitroxyl protected cardiomyocytes against IR injury in an mKATP-dependent manner. Overall, these results suggest that the mKATP channel is activated by specific reactive oxygen and nitrogen species, and inhibited by NADPH. The redox modulation of mKATP may be an underlying mechanism for its regulation in the context of IPC. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► Redox regulation of the mitochondrial KATP channel is poorly understood. ► Superoxide and hydrogen peroxide activated mKATP, while reductants inhibited. ► Many reactive nitrogen species inhibited mKATP, possibly via complex II inhibition. ► NADPH appeared to inhibit mKATP via a mechanism unrelated to its redox potential.
Keywords: K+ channel; Ischemia; Preconditioning; Nitric oxide; Redox;

The mitochondrial permeability transition pore and cyclophilin D in cardioprotection by Fabio Di Lisa; Andrea Carpi; Valentina Giorgio; Paolo Bernardi (1316-1322).
Mitochondria play a central role in heart energy metabolism and Ca2+ homeostasis and are involved in the pathogenesis of many forms of heart disease. The body of knowledge on mitochondrial pathophysiology in living cells and organs is increasing, and so is the interest in mitochondria as potential targets for cardioprotection. This critical review will focus on the permeability transition pore (PTP) and its regulation by cyclophilin (CyP) D as effectors of endogenous protective mechanisms and as potential drug targets. The complexity of the regulatory interactions underlying control of mitochondrial function in vivo is beginning to emerge, and although apparently contradictory findings still exist we believe that the network of regulatory protein interactions involving the PTP and CyPs in physiology and pathology will increase our repertoire for therapeutic interventions in heart disease. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► The permeability transition pore (PTP) is an inner membrane mitochondrial channel. ► Cyclosporin (Cs) A inhibits the pore through Cyclophilin (CyP) D, a matrix protein. ► The PTP is a major target for cardioprotection through CyPD inhibition. ► CyPD regulates other mitochondrial functions in a CsA-sensitive manner. ► We focus on PTP regulation by CyPD as a drug target for cardioprotection.
Keywords: Mitochondria; Heart; Permeability transition; Cyclophilin D; Cardioprotection;

Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury by Nina Kaludercic; Andrea Carpi; Roberta Menabò; Fabio Di Lisa; Nazareno Paolocci (1323-1332).
Recent evidence highlights monoamine oxidases (MAO) as another prominent source of oxidative stress. MAO are a class of enzymes located in the outer mitochondrial membrane, deputed to the oxidative breakdown of key neurotransmitters such as norepinephrine, epinephrine and dopamine, and in the process generate H2O2. All these monoamines are endowed with potent modulatory effects on myocardial function. Thus, when the heart is subjected to chronic neuro-hormonal and/or peripheral hemodynamic stress, the abundance of circulating/tissue monoamines can make MAO-derived H2O2 production particularly prominent. This is the case of acute cardiac damage due to ischemia/reperfusion injury or, on a more chronic stand, of the transition from compensated hypertrophy to overt ventricular dilation/pump failure. Here, we will first briefly discuss mitochondrial status and contribution to acute and chronic cardiac disorders. We will illustrate possible mechanisms by which MAO activity affects cardiac biology and function, along with a discussion as to their role as a prominent source of reactive oxygen species. Finally, we will speculate on why MAO inhibition might have a therapeutic value for treating cardiac affections of ischemic and non-ischemic origin. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► MAOs are one of the major mitochondrial sources of oxidative stress in cardiomyocytes. ► MAO activity contributes to cardiac hypertrophy and extracellular matrix remodeling. ► MAO hyperactivation vivo leads to oxidative stress, apoptosis and heart failure. ► In vivo MAO inhibition prevents heart failure and blunts ischemia/reperfusion injury.
Keywords: Monoamine oxidase; Reactive oxygen species; Myocardial injury; Heart failure; Mitochondria;

Targeting fatty acid and carbohydrate oxidation — A novel therapeutic intervention in the ischemic and failing heart by Jagdip S. Jaswal; Wendy Keung; Wei Wang; John R. Ussher; Gary D. Lopaschuk (1333-1350).
Cardiac ischemia and its consequences including heart failure, which itself has emerged as the leading cause of morbidity and mortality in developed countries are accompanied by complex alterations in myocardial energy substrate metabolism. In contrast to the normal heart, where fatty acid and glucose metabolism are tightly regulated, the dynamic relationship between fatty acid β-oxidation and glucose oxidation is perturbed in ischemic and ischemic–reperfused hearts, as well as in the failing heart. These metabolic alterations negatively impact both cardiac efficiency and function. Specifically there is an increased reliance on glycolysis during ischemia and fatty acid β-oxidation during reperfusion following ischemia as sources of adenosine triphosphate (ATP) production. Depending on the severity of heart failure, the contribution of overall myocardial oxidative metabolism (fatty acid β-oxidation and glucose oxidation) to adenosine triphosphate production can be depressed, while that of glycolysis can be increased. Nonetheless, the balance between fatty acid β-oxidation and glucose oxidation is amenable to pharmacological intervention at multiple levels of each metabolic pathway. This review will focus on the pathways of cardiac fatty acid and glucose metabolism, and the metabolic phenotypes of ischemic and ischemic/reperfused hearts, as well as the metabolic phenotype of the failing heart. Furthermore, as energy substrate metabolism has emerged as a novel therapeutic intervention in these cardiac pathologies, this review will describe the mechanistic bases and rationale for the use of pharmacological agents that modify energy substrate metabolism to improve cardiac function in the ischemic and failing heart. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► Fatty acid and carbohydrate oxidation provide ATP required for cardiac contraction. ► Balance between fatty acid and carbohydrate oxidation affects cardiac efficiency/function. ► Fatty acid oxidation predominates in the post-ischemic and failing heart. ► Interventions can increase carbohydrate oxidation and decrease fatty acid oxidation. ► Increasing carbohydrate oxidation benefits the post-ischemic and failing heart.
Keywords: Ischemia; Heart failure; Cardiac efficiency; Fatty acid oxidation; Glucose oxidation;

Mitochondrial dysfunction in diabetic cardiomyopathy by Jennifer G. Duncan (1351-1359).
Cardiovascular disease is common in patients with diabetes and is a significant contributor to the high mortality rates associated with diabetes. Heart failure is common in diabetic patients, even in the absence of coronary artery disease or hypertension, an entity known as diabetic cardiomyopathy. Evidence indicates that myocardial metabolism is altered in diabetes, which likely contributes to contractile dysfunction and ventricular failure. The mitochondria are the center of metabolism, and recent data suggests that mitochondrial dysfunction may play a critical role in the pathogenesis of diabetic cardiomyopathy. This review summarizes many of the potential mechanisms that lead to mitochondrial dysfunction in the diabetic heart. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► A review of evidence for cardiac mitochondrial abnormalities associated with diabetes. ► Human and animal data supporting mitochondrial dysfunction in diabetic hearts. ► Various mechanisms for mitochondrial dysfunction in diabetic hearts are reviewed.
Keywords: Diabetes; Insulin resistance; Heart failure; Cardiomyopathy; Mitochondria; Oxidative stress; Metabolism;

Bioenergetics of the failing heart by Renée Ventura-Clapier; Anne Garnier; Vladimir Veksler; Frédéric Joubert (1360-1372).
The heart is responsible for pumping blood throughout the blood vessels to the periphery by repeated, rhythmic contractions at variable intensity. As such the heart should permanently adjust energy production to energy utilization and is a high-energy consumer. For this the heart mainly depends on oxidative metabolism for adequate energy production and on efficient energy transfer systems. In heart failure, there is disequilibrium between the work the heart has to perform and the energy it is able to produce to fulfill its needs. This has led to the concept of energy starvation of the failing heart. This includes decreased oxygen and substrate supply, altered substrate utilization, decreased energy production by mitochondria and glycolysis, altered energy transfer and inefficient energy utilization. Mitochondrial biogenesis and its transcription cascade are down-regulated. Disorganization of the cytoarchitecture of the failing cardiomyocyte also participates in energy wastage. Finally, the failing of the cardiac pump, by decreasing oxygen and substrate supply, leads to a systemic energy starvation. Metabolic therapy has thus emerged as an original and promising approach in the treatment heart failure. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► The heart mainly depends on oxidative metabolism for energy production. ► In heart failure, there is disequilibrium between energy production and utilization. ► Mitochondrial biogenesis is down-regulated in heart failure. ► Cytoarchitecture and energy transfer is impaired in heart failure. ► Metabolic therapy is a promising approach in the treatment of heart failure.
Keywords: Cardiac energy metabolism; Mitochondria; Creatine kinase; Compartmentation; Cytoarchitecture;

Mitochondrial Ca2+ influx and efflux rates in guinea pig cardiac mitochondria:Low and high affinity effects of cyclosporine A by An-Chi Wei; Ting Liu; Sonia Cortassa; Raimond L. Winslow; Brian O'Rourke (1373-1381).
Ca2+ plays a central role in energy supply and demand matching in cardiomyocytes by transmitting changes in excitation–contraction coupling to mitochondrial oxidative phosphorylation. Matrix Ca2+ is controlled primarily by the mitochondrial Ca2+ uniporter and the mitochondrial Na+/Ca2+ exchanger, influencing NADH production through Ca2+-sensitive dehydrogenases in the Krebs cycle. In addition to the well-accepted role of the Ca2+-triggered mitochondrial permeability transition pore in cell death, it has been proposed that the permeability transition pore might also contribute to physiological mitochondrial Ca2+ release. Here we selectively measure Ca2+ influx rate through the mitochondrial Ca2+ uniporter and Ca2+ efflux rates through Na+-dependent and Na+-independent pathways in isolated guinea pig heart mitochondria in the presence or absence of inhibitors of mitochondrial Na+/Ca2+ exchanger (CGP 37157) or the permeability transition pore (cyclosporine A). cyclosporine A suppressed the negative bioenergetic consequences (ΔΨm loss, Ca2+ release, NADH oxidation, swelling) of high extramitochondrial Ca2+ additions, allowing mitochondria to tolerate total mitochondrial Ca2+ loads of > 400 nmol/mg protein. For Ca2+ pulses up to 15 μM, Na+-independent Ca2+ efflux through the permeability transition pore accounted for ~ 5% of the total Ca2+ efflux rate compared to that mediated by the mitochondrial Na+/Ca2+ exchanger (in 5 mM Na+). Unexpectedly, we also observed that cyclosporine A inhibited mitochondrial Na+/Ca2+ exchanger-mediated Ca2+ efflux at higher concentrations (IC50  = 2 μM) than those required to inhibit the permeability transition pore, with a maximal inhibition of ~ 40% at 10 μM cyclosporine A, while having no effect on the mitochondrial Ca2+ uniporter. The results suggest a possible alternative mechanism by which cyclosporine A could affect mitochondrial Ca2+ load in cardiomyocytes, potentially explaining the paradoxical toxic effects of cyclosporine A at high concentrations. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► Cyclosporine A (CsA) suppresses the Ca2+-dependent activation of the mitochondrial permeability transition pore (PTP) and protects cells from mitochondrial membrane potential (ΔΨm) loss leading to necrotic or apoptotic cell death. ► Transient PTP opening has been hypothesized to be a physiological mechanism for mitochondrial Ca2+ release and CsA has been reported to increase mitochondrial Ca2+ load. ► The present findings specifically measure Ca2+ influx and efflux rates in isolated guinea pig cardiac mitochondria and show that PTP-mediated Ca2+ efflux is small relative to that mediated by mitochondrial Na+/Ca2+ exchange. ► Concentrations of CsA higher than those required to inhibit the PTP are shown to partially inhibit mitochondrial Na+/Ca2+ exchange. ► The low affinity effect of CsA on mitochondrial Ca2+ efflux may explain, in part, the paradoxical toxic effects of CsA on cardiac myocytes.
Keywords: Mitochondrial Na+/Ca2+ exchanger; Permeability transition pore; Mitochondrial calcium uniporter; Oxidative phosphorylation; Bioenergetics; Calcium transport;

Mitochondrial oxidant stress triggers cell death in simulated ischemia–reperfusion by Gabriel Loor; Jyothisri Kondapalli; Hirotaro Iwase; Navdeep S. Chandel; Gregory B. Waypa; Robert D. Guzy; Terry L. Vanden Hoek; Paul T. Schumacker (1382-1394).
To clarify the relationship between reactive oxygen species (ROS) and cell death during ischemia–reperfusion (I/R), we studied cell death mechanisms in a cellular model of I/R. Oxidant stress during simulated ischemia was detected in the mitochondrial matrix using mito-roGFP, a ratiometric redox sensor, and by Mito-Sox Red oxidation. Reperfusion-induced death was attenuated by over-expression of Mn-superoxide dismutase (Mn-SOD) or mitochondrial phospholipid hydroperoxide glutathione peroxidase (mito-PHGPx), but not by catalase, mitochondria-targeted catalase, or Cu,Zn-SOD. Protection was also conferred by chemically distinct antioxidant compounds, and mito-roGFP oxidation was attenuated by NAC, or by scavenging of residual O2 during the ischemia (anoxic ischemia). Mitochondrial permeability transition pore (mPTP) oscillation/opening was monitored by real-time imaging of mitochondrial calcein fluorescence. Oxidant stress caused release of calcein to the cytosol during ischemia, a response that was inhibited by chemically diverse antioxidants, anoxia, or over-expression of Mn-SOD or mito-PHGPx. These findings suggest that mitochondrial oxidant stress causes oscillation of the mPTP prior to reperfusion. Cytochrome c release from mitochondria to the cytosol was not detected until after reperfusion, and was inhibited by anoxic ischemia or antioxidant administration during ischemia. Although DNA fragmentation was detected after I/R, no evidence of Bax activation was detected. Over-expression of the anti-apoptotic protein Bcl-XL in cardiomyocytes did not confer protection against I/R-induced cell death. Moreover, murine embryonic fibroblasts with genetic depletion of Bax and Bak, or over-expression of Bcl-XL, failed to show protection against I/R. These findings indicate that mitochondrial ROS during ischemia triggers mPTP activation, mitochondrial depolarization, and cell death during reperfusion through a Bax/Bak-independent cell death pathway. Therefore, mitochondrial apoptosis appears to represent a redundant death pathway in this model of simulated I/R. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.► Cardiomyocytes exhibit mitochondrial oxidant stress during simulated ischemia. ► Antioxidants or Mn‐SOD over‐expression attenuate cell death during reperfusion. ► Ischemic triggering of mitochondrial permeability transition requires oxidant stress. ► Knockout of Bax/Bak or cytochrome c fails to protect against cell death in I/R. ► Mitochondrial apoptosis is activated but not required for cell death in this model.
Keywords: Reactive oxygen species; Cardiomyocyte; Permeability transition; roGFP; Apoptosis; Superoxide dismutase;