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The Journal of Neuroscience, June 15, 2003, 23(12):4858-4867

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Increased Susceptibility of Striatal Mitochondria to Calcium-Induced Permeability Transition

Nickolay Brustovetsky,¹ Tatiana Brustovetsky,¹ Kevin J. Purl,¹ Michela Capano,² Martin Crompton,² and Janet M. Dubinsky¹

¹Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and ²Department of Biochemistry and Molecular Biology, University College London, London, WC1E6BT United Kingdom

Mitochondria were simultaneously isolated from striatum and cortex of adult rats and compared in functional assays for their sensitivity to calcium activation of the permeability transition. Striatal mitochondria showed an increased dose-dependent sensitivity to Ca²⁺ compared with cortical mitochondria, as measured by mitochondrial depolarization, swelling, Ca²⁺ uptake, reactive oxygen species production, and respiration. Ratios of ATP to ADP were lower in striatal mitochondria exposed to calcium despite equal amounts of ADP and ATP under respiring and nonrespiring conditions. The Ca²⁺-induced changes were inhibited by cyclosporin A or ADP. These responses are consistent with Ca²⁺ activation of both low and high permeability pathways constituting the mitochondrial permeability transition. In addition to the striatal supersensitivity to induction of the permeability transition, cyclosporin A inhibition was less potent in striatal mitochondria. Immunoblots indicated that striatal mitochondria contained more cyclophilin D than cortical mitochondria. Thus striatal mitochondria may be selectively vulnerable to the permeability transition. Subsequent mitochondrial dysfunction could contribute to the initial toxicity of striatal neurons in Huntington's disease.

Key words: permeability transition; brain mitochondria; Huntington's disease; neurotoxicity; regional differences; cyclophilin D

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Received Jan. 13, 2003; revised Mar. 24, 2003; accepted Mar. 26, 2003.

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