NDUFA4 Is a Subunit of Complex IV of the Mammalian Electron Transport Chain

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (162 K)Download as PowerPoint slideHighlights► NDUFA4 physically interacts with complex IV and not with complex I ► Absence of NDUFA4 does not perturb CI but instead reduces CIV amount and activity ► NDUFA4 coevolved with complex IV and not with complex I