Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes

The mammalian respiratory chain complexes I, III2, and IV (CI, CIII2, and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI-CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and the regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knockin mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in mice but raise questions about their alternate functions, such as those relating to the regulation of protein stability and prevention of age-associated protein aggregation. [Display omitted] •Three amino acids (EED) in UQCRC1 of complex III2 control respirasome stability•Homozygous Uqcrc1delEED knockin mice have drastically reduced respirasome levels•Profound depletion of respirasomes does not impair oxidative phosphorylation•Mice with a profound depletion of respirasomes have apparently normal physiology The role of the mammalian respirasome, a stable assembly of a complete respiratory chain, is much debated. Milenkovic et al. have generated knockin mice with a profound depletion of respirasomes. Very unexpectedly, the mutant mice have preserved oxidative phosphorylation capacity and physiology, arguing that respirasomes may be dispensable for normal bioenergetics.