Apoptosis in Heart and Skeletal Muscle

2002 ◽  
Vol 27 (4) ◽  
pp. 349-395 ◽  
Author(s):  
Andy J. Primeau ◽  
Peter J. Adhihetty ◽  
David A. Hood
Keyword(s):  
Reactive Oxygen Species ◽  
Skeletal Muscle ◽  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Permeability Transition ◽  
Current Evidence ◽  
Oxygen Species ◽  
Cellular Mechanisms

Apoptosis, or programmed cell death, is now recognized to be an important cellular event during normal development and in the progression of specific diseases. Apoptosis can be triggered by stimuli initiating outside of the cell, or within the mitochondria, leading to the activation of caspases and subsequent cell death. Although apoptosis has been widely studied in a variety of tissues over the last 5 years, skeletal muscle and heart have been relatively ignored in this regard. Research on apoptosis in cardiac muscle has recently taken on a higher profile as the recognition emerges that it may be an important contributor to specific cardiac pathologies, particularly in response to ischemia-reperfusion in which reactive oxygen species are formed. In skeletal muscle, very few studies have been done under specific physiological (e.g., exercise) and pathophysiological (e.g., dystrophies, denervation, myopathies) conditions. Skeletal muscle is unique in that it is mutli-nucleated, and evidence suggests that it can undergo individual myonuclear apoptosis as well as complete cell death. This review discusses the basic cellular mechanisms of apoptosis, as well as the current evidence of this process in cardiac and skeletal muscle. The need for more work in this area is highlighted, particularly in exercise and training. Key words: transcription factors, reactive oxygen species, mitochondria, caspase, mitochondrial permeability transition

Mitochondrial permeability transition in hepatocytes induced by t-BuOOH: NAD(P)H and reactive oxygen species

1997 ◽  
Vol 272 (4) ◽  
pp. C1286-C1294 ◽  
Author(s):  
A. L. Nieminen ◽  
A. M. Byrne ◽  
B. Herman ◽  
J. J. Lemasters
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Reactive Oxygen ◽  
Permeability Transition ◽  
Cell Killing ◽  
Second Phase ◽  
Oxygen Species ◽  
Mitochondrial Permeability ◽  
Ros Formation

Tert-butyl hydroperoxide (t-BuOOH) induces the mitochondrial permeability transition (MPT) in hepatocytes, leading to cell death. Using confocal microscopy, we visualized pyridine nucleotide oxidation and reactive oxygen species (ROS) formation induced by t-BuOOH. Reduced mitochondrial pyridine nucleotides (NADH and NADPH) were imaged by autofluorescence. Mitochondrial membrane potential, ROS, onset of MPT, and cell death were monitored with tetramethylrhodamine methyl ester (TMRM), dichlorofluorescin, calcein, and propidium iodide, respectively. t-BuOOH rapidly oxidized mitochondrial NAD(P)H. Oxidation was biphasic, and the second slower phase occurred during mitochondrial ROS generation. Subsequently, MPT took place, mitochondria depolarized, and cells died. beta-Hydroxybutyrate, which reduces mitochondrial NAD+, delayed cell killing, but lactate, which reduces cytosolic NAD+, did not. Trifluoperazine, which inhibits MPT, did not block the initial oxidation of NAD(P)H but prevented the second phase of oxidation, partially blocked ROS formation, and preserved cell viability. The antioxidants, deferoxamine and diphenylphenylenediamine, also prevented the second phase of NAD(P)H oxidation. They also blocked ROS formation nearly completely and stopped cell killing. Both antioxidants also prevented the mitochondrial permeability transition and subsequent mitochondrial depolarization. In conclusion, NAD(P)H oxidation and ROS formation are critical events promoting MPT in oxidative injury and death of hepatocytes.

scholarly journals Mitochondrial permeability transition in rat hepatocytes after anoxia/reoxygenation: role of Ca2+-dependent mitochondrial formation of reactive oxygen species

2012 ◽  
Vol 302 (7) ◽  
pp. G723-G731 ◽  
Author(s):  
Jae-Sung Kim ◽  
Jin-Hee Wang ◽  
John J. Lemasters
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Rat Hepatocytes ◽  
Oxygen Species ◽  
Mitochondrial Permeability ◽  
Ros Formation

Onset of the mitochondrial permeability transition (MPT) is the penultimate event leading to lethal cellular ischemia-reperfusion injury, but the mechanisms precipitating the MPT after reperfusion remain unclear. Here, we investigated the role of mitochondrial free Ca2+ and reactive oxygen species (ROS) in pH- and MPT-dependent reperfusion injury to hepatocytes. Cultured rat hepatocytes were incubated in anoxic Krebs-Ringer-HEPES buffer at pH 6.2 for 4 h and then reoxygenated at pH 7.4 to simulate ischemia-reperfusion. Some cells were loaded with the Ca2+ chelators, BAPTA/AM and 2-[(2-bis-[carboxymethyl]aono-5-methoxyphenyl)-methyl-6-methoxy-8-bis[carboxymethyl]aminoquinoline, either by a cold loading protocol for intramitochondrial loading or by warm incubation for cytosolic loading. Cell death was assessed by propidium iodide fluorometry and immunoblotting. Mitochondrial Ca2+, inner membrane permeability, membrane potential, and ROS formation were monitored with Rhod-2, calcein, tetramethylrhodamine methylester, and dihydrodichlorofluorescein, respectively. Necrotic cell death increased after reoxygenation. Necrosis was blocked by 1 μM cyclosporin A, an MPT inhibitor, and by reoxygenation at pH 6.2. Confocal imaging of Rhod-2, calcein, and dichlorofluorescein revealed that an increase of mitochondrial Ca2+ and ROS preceded onset of the MPT after reoxygenation. Intramitochondrial Ca2+ chelation, but not cytosolic Ca2+ chelation, prevented ROS formation and subsequent necrotic and apoptotic cell death. Reoxygenation with the antioxidants, desferal or diphenylphenylenediamine, also suppressed MPT-mediated cell death. However, inhibition of cytosolic ROS by apocynin or diphenyleneiodonium chloride failed to prevent reoxygenation-induced cell death. In conclusion, Ca2+-dependent mitochondrial ROS formation is the molecular signal culminating in onset of the MPT after reoxygenation of anoxic hepatocytes, leading to cell death.

scholarly journals Phospholipid oxidation products in ferroptotic myocardial cell death

2019 ◽  
Vol 317 (1) ◽  
pp. H156-H163 ◽  
Author(s):  
Aleksandra Stamenkovic ◽  
Grant N. Pierce ◽  
Amir Ravandi
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Myocardial Cell ◽  
Oxidation Products ◽  
Oxygen Species ◽  
New Therapeutic Approaches

Cell death is an important component of the pathophysiology of any disease. Myocardial disease is no exception. Understanding how and why cells die, particularly in the heart where cardiomyocyte regeneration is limited at best, becomes a critical area of study. Ferroptosis is a recently described form of nonapoptotic cell death. It is an iron-mediated form of cell death that occurs because of accumulation of lipid peroxidation products. Reactive oxygen species and iron-mediated phospholipid peroxidation is a hallmark of ferroptosis. To date, ferroptosis has been shown to be involved in cell death associated with Alzheimer’s disease, Huntington’s disease, cancer, Parkinson’s disease, and kidney degradation. Myocardial reperfusion injury is characterized by iron deposition as well as reactive oxygen species production. These conditions, therefore, favor the induction of ferroptosis. Currently there is no available treatment for reperfusion injury, which accounts for up to 50% of the final infarct size. This review will summarize the evidence that ferroptosis can induce cardiomyocyte death following reperfusion injury and the potential for this knowledge to open new therapeutic approaches for myocardial ischemia-reperfusion injury.

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