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J. Biol. Chem., Vol. 282, Issue 33, 24373-24380, August 17, 2007

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Zinc Irreversibly Damages Major Enzymes of Energy Production and Antioxidant Defense Prior to Mitochondrial Permeability Transition^*

Irina G. Gazaryan, Inna P. Krasinskaya, Bruce S. Kristal, and Abraham M. Brown^¶1

From the Burke Medical Research Institute, White Plains, New York 10605 and the Departments of Neuroscience and ^¶Biochemistry, Weill Medical College of Cornell University, New York, New York 10021

Recent observations point to the role played by Zn²⁺ as an inducer of neuronal death. Two Zn²⁺ targets have been identified that result in inhibition of mitochondrial respiration: the bc₁ center and, more recently, -ketoglutarate dehydrogenase. Zn²⁺ is also a mediator of oxidative stress, leading to mitochondrial failure, release of apoptotic peptides, and neuronal death. We now present evidence, by means of direct biochemical assays, that Zn²⁺ is imported through the Ca²⁺ uniporter and directly targets major enzymes of energy production (lipoamide dehydrogenase) and antioxidant defense (thioredoxin reductase and glutathione reductase). We demonstrate the following. (a) These matrix enzymes are rapidly inhibited by application of Zn²⁺ to intact mitochondria. (b) Delayed treatment with membrane-impermeable chelators has no effect, indicating rapid transport of biologically relevant quantities of Zn²⁺ into the matrix. (c) Membrane-permeable chelators stop but do not reverse enzyme inactivation. (d) Enzyme inhibition is rapid and irreversible and precedes the major changes associated with the mitochondrial permeability transition (MPT). (e) The extent and rate of enzyme inactivation linearly correlates with the MPT onset and propagation. (f) The Ca²⁺ uniporter blocker, Ruthenium Red, protects enzyme activities and delays pore opening up to 2 µM Zn²⁺. An additional, unidentified import route functions at higher Zn²⁺ concentrations. (g) No enzyme inactivation is observed for Ca²⁺-induced MPT. These observations strongly suggest that, unlike Ca²⁺, exogenous Zn²⁺ interferes with mitochondrial NADH production and directly alters redox protection in the matrix, contributing to mitochondrial dysfunction. Inactivation of these enzymes by Zn²⁺ is irreversible, and thus only their de novo synthesis can restore function, which may underlie persistent loss of oxidative carbohydrate metabolism following transient ischemia.

Received for publication, December 12, 2006 , and in revised form, May 17, 2007.

^* This work was supported by National Institutes of Health NINDS Grant NS38741 (to A. M. 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.

¹ To whom correspondence should be addressed: Dementia Research Service, Burke Medical Research Institute, 785 Mamaroneck Ave., White Plains, NY 10605. Tel.: 914-597-2327; Fax: 914-597-2757; E-mail: ambrown{at}med.cornell.edu.

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