Human COX7A2L Regulates Complex III Biogenesis and Promotes Supercomplex Organization Remodeling without Affecting Mitochondrial Bioenergetics

摘要

h2 class="section-title"Summary/h2 p id="abspara0010"The mitochondrial respiratory chain is organized in?a?dynamic set of supercomplexes (SCs). The COX7A2L protein is essential for mammalian SC IIIsub2/sub+IV assembly. However, its function in respirasome (SCs?I+IIIsub2/sub+IVsubn/sub) biogenesis remains controversial. To?unambiguously determine the COX7A2L role, we?generated COX7A2L -knockout ( COX7A2L -KO) HEK293T and U87 cells. COX7A2L -KO cells lack SC IIIsub2/sub+IV but have enhanced complex III steady-state levels, activity, and assembly rate, normal de novo complex IV biogenesis, and delayed respirasome formation. Nonetheless, the KOs have normal respirasome steady-state levels, and only larger structures (SCs Isub1-2/sub+IIIsub2/sub+IVsub2-n/sub or megacomplexes) were undetected. Functional substrate-driven competition assays showed normal mitochondrial respiration in COX7A2L -KO cells in standard and nutritional-, environmental-, and oxidative-stress-challenging conditions. We conclude that COX7A2L establishes a regulatory checkpoint for the biogenesis of CIIIsub2/sub and specific SCs, but the COX7A2L-dependent MRC remodeling is essential neither to maintain mitochondrial bioenergetics nor to cope with acute cellular stresses.