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J. Biol. Chem., Vol. 282, Issue 24, 17442-17449, June 15, 2007

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Evidence for a Pro-oxidant Intermediate in the Assembly of Cytochrome Oxidase^*

From the University of Utah Health Sciences Center, Departments of Medicine and Biochemistry, Salt Lake City, Utah 84132

The hydrogen peroxide sensitivity of cells lacking two proteins, Sco1 and Cox11, important in the assembly of cytochrome c oxidase (CcO), is shown to arise from the transient accumulation of a pro-oxidant heme A-Cox1 stalled intermediate. The peroxide sensitivity of these cells is abrogated by a reduction in either Cox1 expression or heme A formation but exacerbated by either enhanced Cox1 expression or heme A production arising from overexpression of COX15. Sco1 and Cox11 are implicated in the formation of the Cu_A and Cu_B sites of CcO, respectively. The respective wild-type genes suppress the peroxide sensitivities of sco1 and cox11 cells, but no cross-complementation is seen with noncognate genes. Copper-binding mutant alleles of Sco1 and Cox11 that are nonfunctional in promoting the assembly of CcO are functional in suppressing the peroxide sensitivity of their respective null mutants. Likewise, human Sco1 that is nonfunctional in yeast CcO assembly is able to suppress the peroxide sensitivity of yeast sco1 cells. Thus, a disconnect exists between the respiratory capacity of cells and hydrogen peroxide sensitivity. Hydrogen peroxide sensitivity of sco1 and cox11 cells is abrogated by overexpression of a novel mitochondrial ATPase Afg1 that promotes the degradation of CcO mitochondrially encoded subunits. Studies on the hydrogen peroxide sensitivity in CcO assembly mutants reveal new aspects of the CcO assembly process.

Received for publication, March 20, 2007 , and in revised form, April 11, 2007.

^* This work was supported by National Institutes of Health Grant ES03817 (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 Figs. S1 and S2 and Table 1.

¹ To whom correspondence should be addressed: University of Utah Health Sciences Center, Salt Lake City, UT 84132. Tel.: 801-585-5103; Fax: 801-585-5469; E-mail: dennis.winge{at}hsc.utah.edu.

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