mtDNA Mutations Confer Cellular Sensitivity to Oxidant Stress That Is Partially Rescued by Calcium Depletion and Cyclosporin A

doi:10.1006/bbrc.1997.7443

Biochemical and Biophysical Research Communications

Volume 239, Issue 1, 9 October 1997, Pages 139-145

https://doi.org/10.1006/bbrc.1997.7443 Get rights and content

Abstract

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 H₂O₂exposure 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 Ca²⁺-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.

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¹: Address correspondence to Dr. Gino Cortopassi. Fax: (916) 754-9342. E-mail: [email protected].

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Regular ArticlemtDNA Mutations Confer Cellular Sensitivity to Oxidant Stress That Is Partially Rescued by Calcium Depletion and Cyclosporin A

Abstract

Regular Article
mtDNA Mutations Confer Cellular Sensitivity to Oxidant Stress That Is Partially Rescued by Calcium Depletion and Cyclosporin A