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The Journal of Neuroscience, September 15, 2004, 24(37):8019-8028; doi:10.1523/JNEUROSCI.1103-04.2004

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Neurobiology of Disease
Highly Selective and Prolonged Depletion of Mitochondrial Glutathione in Astrocytes Markedly Increases Sensitivity to Peroxynitrite

Håkan Muyderman,^1,2 Michael Nilsson,² and Neil R. Sims¹

¹Centre for Neuroscience, Flinders Institute for Health and Medical Research, and Department of Medical Biochemistry, School of Medicine, Flinders University, 5001 Adelaide, Australia, and ²Arvid Carlsson Institute for Neuroscience, Institute of Clinical Neuroscience, Göteborg University, 405 30 Göteborg, Sweden

Glutathione, a major endogenous antioxidant, is found in two intracellular pools in the cytoplasm and the mitochondria. To investigate the importance of the smaller mitochondrial pool, we developed conditions based on treatment with ethacrynic acid that produced near-complete and highly selective depletion of mitochondrial glutathione in cultured astrocytes. Recovery of mitochondrial glutathione was only partial over several hours, suggesting slow net uptake from the cytoplasm. Glutathione depletion alone did not significantly affect mitochondrial membrane potential, ATP content, or cell viability when assessed after 24 hr, although the activities of respiratory chain complexes were altered. However, these astrocytes showed a greatly enhanced sensitivity to 3-morpholinosydnonimine, a peroxynitrite generator. Treatment with 200 µM 3-morpholinosydnonimine produced decreases within 3 hr in mitochondrial membrane potential and ATP content and caused the release of lactate dehydrogenase, contrasting with preservation of these properties in control cells. These properties deteriorated further by 24 hr in the glutathione-depleted cells and were associated with morphological changes indicative of necrotic cell death. This treatment enhanced the alterations in activities of the respiratory chain complexes observed with glutathione depletion alone. Cell viability was markedly improved by cyclosporin A, suggesting a role for the mitochondrial permeability transition in the astrocytic death. These studies provide the most direct evidence available for any cell type on the roles of mitochondrial glutathione. They demonstrate the critical importance of this metabolite pool in protecting against peroxynitrite-induced damage in astrocytes and indicate a key contribution in determining the activities of respiratory chain components.

Key words: glutathione; SIN-1; astrocytes; mitochondria; cyclosporin A; peroxynitrite

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Received Dec 15, 2003; revised June 23, 2004; accepted July 7, 2004.

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