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J. Biol. Chem., Vol. 283, Issue 18, 12267-12275, May 2, 2008

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Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein^*

Marjatta Son, Scot C. Leary, Nadine Romain^¶, Fabien Pierrel^||, Dennis R. Winge^||, Ronald G. Haller^¶**, and Jeffrey L. Elliott¹

From the Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Montreal Neurological Institute and McGill University, Montreal H3A 2B4, Canada, ^¶Institute for Exercise and Environmental Medicine, Dallas, Texas 75232, ^**Dallas Veterans Affairs Medical Center, Dallas, Texas 75216, and ^||Departments of Medicine and Biochemistry, University of Utah Health Sciences Center, Salt Lake City, Utah 84132

G93A SOD1 transgenic mice overexpressing CCS protein develop an accelerated disease course that is associated with enhanced mitochondrial pathology and increased mitochondrial localization of mutant SOD1. Because these results suggest an effect of mutant SOD1 on mitochondrial function, we assessed the enzymatic activities of mitochondrial respiratory chain complexes in the spinal cords of CCS/G93A SOD1 and control mice. CCS/G93A SOD1 mouse spinal cord demonstrates a 55% loss of complex IV (cytochrome c oxidase) activity compared with spinal cord from age-matched non-transgenic or G93A SOD1 mice. In contrast, CCS/G93A SOD1 spinal cord shows no reduction in the activities of complex I, II, or III. Blue native gel analysis further demonstrates a marked reduction in the levels of complex IV but not of complex I, II, III, or V in spinal cords of CCS/G93A SOD1 mice compared with non-transgenic, G93A SOD1, or CCS/WT SOD1 controls. With SDS-PAGE analysis, spinal cords from CCS/G93A SOD1 mice showed significant decreases in the levels of two structural subunits of cytochrome c oxidase, COX1 and COX5b, relative to controls. In contrast, CCS/G93A SOD1 mouse spinal cord showed no reduction in levels of selected subunits from complexes I, II, III, or V. Heme A analyses of spinal cord further support the existence of cytochrome c oxidase deficiency in CCS/G93A SOD1 mice. Collectively, these results establish that CCS/G93A SOD1 mice manifest an isolated complex IV deficiency which may underlie a substantial part of mutant SOD1-induced mitochondrial cytopathy.

Received for publication, October 15, 2007 , and in revised form, March 7, 2008.

^* This work was supported by grants from the Muscular Dystrophy Association (to J. L. E., S. C. L., and R. G. H.), the Horace C. Cabe Foundation (to J. L. E.), the Judith and Jean Pape Adams Charitable Foundation (to J. L. E.), Veterans Affairs Merit Review (to R. G. H.), and National Institutes of Health Grants NS055315 (to J. L. E.) and GM083292 (to D. R. W.). 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 Fig. 1.

¹ To whom correspondence should be addressed: 5323 Harry Hines Blvd., Dallas, TX 75390. Tel.: 214-645-6242; Fax: 214-645-6238; E-mail: Jeffrey.elliott{at}utsouthwestern.edu.

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