|
|
THE ROLE OF MITOCHONDRIA IN MUSCLE CELL DEATH W. Irwin, E. Fontaine and P.
Bernardi
Mitochondria, the main sources of energy for eukaryotic cells, through oxidative phosphorylation, also play a role in pathways leading to cell death. The mode of cell death may be influenced by the availability of ATP, and its very occurence may critically depend on release of mitochondrial proteins like cytochrome c, apoptosis-inducing factor and caspases. Calcium-dependent onset of the permeability transition, caused by opening of a cyclosporin A-sensitive pore modulated by cyclophillin D, may play a major role in cell death through ATP depletion, dysruption of calcium homeostasis, and possibly through the release of the above-mentioned proteins. Dysregulation of calcium homeostasis, proteolysis and a decreased ability to cope with oxidative stress are clearly involved in the pathogenesis of Duchenne's Muscular Dystrophy (DMD), downstream of the genetic lesion. Mitochondria appear as likely targets that may amplify the initial insult, resulting in the irreversible events leading to cell demise. We have identified novel inhibitors of the permeability transition pore that are effective in skeletal muscle mitochondria and validated bupivacaine in a short-term model of muscle cell death involving mitochondrial depolarization and pore opening as early events. Of particular relevance appear to be the differences between fibers of the striated portion of the esophagus (which in DMD is spared from the disease despite the genetic lesion) and of skeletal muscle (which undergoes calcium dysregulation and cell death). Our results show that esophagus striated muscle fibers are resistant to bupivacaine toxicity in culture, a condition that leads to calcium de-regulation and hypercontracture of skeletal muscle cells and results in cell death. The basis for this striking difference, which correlates with the resistance to degeneration of this type of muscle in DMD, is under active investigation.
For further information contact...Carmen Mannella: carmen@wadsworth.org |
||