mtDNA mutations confer cellular sensitivity to oxidant stress that is partially rescued by calcium depletion and cyclosporin A.
The complete mechanism by which pathogenic mtDNA mutations cause cellular pathophysiology and in some cases cell death is unclear. Oxidant stress is especially toxic to excitable nerve and muscle cells, cells that are often affected in mitochondrial disease. The sensitivity of cells bearing the LHON, MELAS, and MERRF mutations to oxidant stress was determined. All were significantly more sensitive to H2O2 exposure than their nonmutant cybrid controls, the order of sensitivity was MELAS > LHON > MERRF > controls. Depletion of Ca2+ from the medium protected all cell lines from oxidant stress, consistent with the hypothesis that death induced by oxidant stress is Ca(2+)-dependent. A potential downstream target of Ca2+ is the mitochondrial permeability transition, MPT, which is inhibited by cyclosporin A. Treatment of MELAS, LHON, and MERRF cells with cyclosporin A caused significant rescue from oxidant exposure, and in each case significantly greater rescue of mutant than control cells. The pronounced oxidant-sensitivity of mutant cells, and their protection by Ca2+ depletion and CsA, has potential implications for both the pathophysiological mechanism and therapy of these mitochondrial genetic diseases.
Wong
A
A
Department of Molecular Biosciences, University of California, Davis 95616, USA.
Cortopassi
G
G
D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017241:MELAS Syndrome / Q000235:genetics / Q000378:metabolism; D017243:MERRF Syndrome / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D015418:Optic Atrophies, Hereditary / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*
D004272:DNA, Mitochondrial; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D006861:Hydrogen Peroxide; D002118:Calcium