The oxidative phosphorylation system is one of the best-characterized metabolic pathways. In mammals, the protein components and X-ray structures are defined for all complexes except complex I. Here, we show that NDUFA4, formerly considered a constituent of NADH Dehydrogenase (CI), is instead a component of the cytochrome c oxidase (CIV). Deletion of NDUFA4 does not perturb CI. Rather, proteomic, genetic, evolutionary, and biochemical analyses reveal that NDUFA4 plays a role in CIV function and biogenesis. The change in the attribution of the NDUFA4 protein requires renaming of the gene and reconsideration of the structure of CIV. Furthermore, NDUFA4 should be considered a candidate gene for CIV rather than CI deficiencies in humans.
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