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J. Biol. Chem., Vol. 281, Issue 42, 31950-31962, October 20, 2006

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Mitochondrial Protein Nitration Primes Neurodegeneration in Experimental Autoimmune Encephalomyelitis^*

Xiaoping Qi, Alfred S. Lewin, Liang Sun, William W. Hauswirth, and John Guy^¶1

From the Departments of Ophthalmology, Molecular Genetics and Microbiology, and ^¶Neurology, the University of Florida College of Medicine, Gainesville, Florida 32610-0284

The mechanisms of axonal and neuronal degeneration causing visual and neurologic disability in multiple sclerosis are poorly understood. Here we explored the contribution of mitochondria to neurodegeneration in the experimental autoimmune encephalomyelitis animal model of multiple sclerosis. Oxidative injury to the murine mitochondrion preceded the infiltration of inflammatory cells, classically heralded as the mediators of demyelination and axonal injury by transection. Nitration of mitochondrial proteins affected key subunits of complexes I and IV of the respiratory chain and a chaperone critical to the stabilization and translocation of proteins into the organelle. Oxidative products were associated with loss of mitochondrial membrane potential and apoptotic cell death. Reductions in the rate of synthesis of adenosine triphosphate were severe and even greater than those associated with disorders caused by mutated mitochondrial DNA. Mitochondrial vacuolization, swelling, and dissolution of cristae occurred in axons as early as 3 days after sensitization for experimental autoimmune encephalomyelitis. Our findings implicate mitochondrial dysfunction induced by protein inactivation and mediated by oxidative stress initiates a cascade of molecular events leading to apoptosis and neurodegeneration in experimental autoimmune encephalomyelitis that is not mediated by inflammatory cells.

Received for publication, April 18, 2006 , and in revised form, August 7, 2006.

^* This work was supported by National Institutes of Health Grants EY07982 (to J. G.) and EY12355 (to J. G.) and Research to Prevent Blindness (to J. G.). 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 and reprint requests should be addressed: Dept. of Ophthalmology, University of Florida, Box 100284, Gainesville, FL 32610-0284. Tel.: 352-846-2102; Fax: 352-392-7839; E-mail: johnguy{at}eye.ufl.edu.

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