Mitochondria in muscle cell death.
Mitochondria, the main source of energy for eukaryotic cells through oxidative phosphorylation, also play a key role in the pathways to cell death. The mode of cell death may be influenced by the availability of ATP, and its very occurrence may critically depend on release of mitochondrial proteins like cytochrome c, apoptosis-inducing factor and possibly caspases 3 and 9. Ca2+-dependent onset of the permeability transition, caused by opening of a cyclosporin A-sensitive pore modulated by cyclophilin D, may play a major role in cell death through ATP depletion, disruption of Ca2+ homeostasis, and release of specific mitochondrial proteins. Dysregulation of Ca2+ homeostasis, proteolysis and a decreased ability to cope with oxidative stress are involved in the pathogenesis of Duchenne's muscular dystrophy downstream of the genetic lesion, and mitochondria appear as likely targets that may amplify the initial insult resulting in the irreversible events leading to cell demise. My colleagues and I are studying the permeability transition in skeletal muscle mitochondria, and we are validating bupivacaine in a short-term model of muscle cell toxicity involving mitochondrial depolarization and pore opening as early events. Specific goals for the future are to further define the role of mitochondria in muscle cell death, with particular emphasis on the role of the permeability transition pore and cyclophilin D, and to develop and test drugs able to affect its course in model systems in vitro and in the mdx mouse, an animal model of Duchenne's muscular dystrophy.
Department of Biomedical Sciences, University of Padova, Italy.
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Bernardi
D000818:Animals; D017209:Apoptosis; D002045:Bupivacaine / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D004734:Energy Metabolism; D006801:Humans; D020104:Immunophilins / Q000502:physiology; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000378:metabolism* / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D051381:Rats
D000081406:Peptidyl-Prolyl Isomerase F; D009124:Muscle Proteins; C000631446:PPIF protein, mouse; D021983:Cyclophilins; D020104:Immunophilins; D002118:Calcium; D002045:Bupivacaine