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J. Biol. Chem., Vol. 282, Issue 19, 14186-14193, May 11, 2007

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Mitochondria Are a Major Source of Paraquat-induced Reactive Oxygen Species Production in the Brain^*

From the Department of Pharmaceutical Sciences, University of Colorado at Denver and Health Sciences Center, Denver, Colorado 80262

Paraquat (PQ²⁺) is a prototypic toxin known to exert injurious effects through oxidative stress and bears a structural similarity to the Parkinson disease toxicant, 1-methyl-4-pheynlpyridinium. The cellular sources of PQ²⁺-induced reactive oxygen species (ROS) production, specifically in neuronal tissue, remain to be identified. The goal of this study was to determine the involvement of brain mitochondria in PQ²⁺-induced ROS production. Highly purified rat brain mitochondria were obtained using a Percoll density gradient method. PQ²⁺-induced hydrogen peroxide (H₂O₂) production was measured by fluorometric and polarographic methods. The production of H₂O₂ was evaluated in the presence of inhibitors and modulators of the mitochondrial respiratory chain. The results presented here suggest that in the rat brain, (a) mitochondria are a principal cellular site of PQ²⁺-induced H₂O₂ production, (b) PQ²⁺-induced H₂O₂ production requires the presence of respiratory substrates, (c) complex III of the electron transport chain is centrally involved in H₂O₂ production by PQ²⁺, and (d) the mechanism by which PQ²⁺ generates H₂O₂ depends on the mitochondrial inner transmembrane potential. These observations were further confirmed by measuring PQ²⁺-induced H₂O₂ production in primary neuronal cells derived from the midbrain. These findings shed light on the mechanism through which mitochondria may contribute to ROS production by other environmental and endogenous redox cycling agents implicated in Parkinson's disease.

Received for publication, January 29, 2007 , and in revised form, March 19, 2007.

^* This work was supported by National Institutes of Health Grant NS045748 (to M. P.) and an American Foundation for Pharmaceutical Education predoctoral fellowship (to D. A. D.). 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: Dept. of Pharmaceutical Sciences, 4200 East Ninth Ave., School of Pharmacy, C238, Denver, CO 80262. Tel.: 303-315-2973; Fax: 303-315-6281; E-mail: manisha.patel{at}uchsc.edu.

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