COX7A2L Is a Mitochondrial Complex III Binding Protein that Stabilizes the III2+IV Supercomplex without Affecting Respirasome Formation

Mitochondrial respiratory chain (MRC) complexes I, III, and IV associate into a variety of supramolecular structures known as supercomplexes and respirasomes. While COX7A2L was originally described as a supercomplex-specific factor responsible for the dynamic association of complex IV into these structures to adapt MRC function to metabolic variations, this role has been disputed. Here, we further examine the functional significance of COX7A2L in the structural organization of the mammalian respiratory chain. As in the mouse, human COX7A2L binds primarily to free mitochondrial complex III and, to a minor extent, to complex IV to specifically promote the stabilization of the III+IV supercomplex without affecting respirasome formation. Furthermore, COX7A2L does not affect the biogenesis, stabilization, and function of the individual oxidative phosphorylation complexes. These data show that independent regulatory mechanisms for the biogenesis and turnover of different MRC supercomplex structures co-exist.Instituto de Salud Carlos III (grant numbers PI11-00182 and PI14-00209 to C.U., PI12-01683 to M.A.M., and PI12-00933 to S.C.), by Comunidad Autónoma de Madrid (P2010/BMD-2361 to C.U. and P2010/BMD-2402 to M.A.M. and S.C.), by European FEDER Funds, by Association Française contre les Myopathies (16086) to E.F.V., by an European Research Council advanced investigator grant (268897) and grants from the Deutsche Forschungsgemeinschaft (SFB829) and the Swedish Research Council (2015-00418) to N.G.L., and by NIH-NIGMS (1R01GM105781-01) to C.U.Peer Reviewe