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J. Biol. Chem., Vol. 282, Issue 25, 18057-18068, June 22, 2007

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Lithium Desensitizes Brain Mitochondria to Calcium, Antagonizes Permeability Transition, and Diminishes Cytochrome c Release^*

Natalia Shalbuyeva, Tatiana Brustovetsky, and Nickolay Brustovetsky¹

From the Department of Pharmacology and Toxicology and Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202

Among the numerous effects of lithium on intracellular targets, its possible action on mitochondria remains poorly explored. In the experiments with suspension of isolated brain mitochondria, replacement of KCl by LiCl suppressed mitochondrial swelling, depolarization, and a release of cytochrome c induced by a single Ca²⁺ bolus. Li⁺ robustly protected individual brain mitochondria loaded with rhodamine 123 against Ca²⁺-induced depolarization. In the experiments with slow calcium infusion, replacement of KCl by LiCl in the incubation medium increased resilience of synaptic and nonsynaptic brain mitochondria as well as resilience of liver and heart mitochondria to the deleterious effect of Ca²⁺. In LiCl medium, mitochondria accumulated larger amounts of Ca²⁺ before they lost the ability to sequester Ca²⁺. However, lithium appeared to be ineffective if mitochondria were challenged by Sr²⁺ instead of Ca²⁺. Cyclosporin A, sanglifehrin A, and Mg²⁺, inhibitors of the mitochondrial permeability transition (mPT), increased mitochondrial Ca²⁺ capacity in KCl medium but failed to do so in LiCl medium. This suggests that the mPT might be a common target for Li⁺ and mPT inhibitors. In addition, lithium protected mitochondria against high Ca²⁺ in the presence of ATP, where cyclosporin A was reported to be ineffective. SB216763 and SB415286, inhibitors of glycogen synthase kinase-3, which is implicated in regulating reactive oxygen species-induced mPT in cardiac mitochondria, did not increase Ca²⁺ capacity of brain mitochondria. Altogether, these findings suggest that Li⁺ desensitizes mitochondria to elevated Ca²⁺ and diminishes cytochrome c release from brain mitochondria by antagonizing the Ca²⁺-induced mPT.

Received for publication, March 12, 2007 , and in revised form, April 18, 2007.

^* This work was supported by NINDS, National Institutes of Health, Grant R01 NS 050131 (to N. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

¹ To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Dr., Medical Science Bldg. Rm. 549, Indianapolis, IN 46202. Tel.: 317-278-9229; Fax: 317-274-7714; E-mail: nbrous{at}iupui.edu.

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