Post-assembly proteostasis of the respiratory chain is independent of respirasome organization

Abstract

Respirasomes have long been proposed to stabilize their constituent complexes. Yet the close relationship between individual complex biogenesis and respirasome formation has made it difficult to determine whether respirasomes are required for complex maintenance after assembly. Here, we uncoupled these processes using a genetic perturbation of the CI-CIII2 contact site that severely depletes respirasomes while preserving individual complex assembly and function. Across orthogonal measures of protein stability, turnover and solubility, respiratory-chain maintenance remained largely preserved despite severe respirasome depletion in mouse embryonic fibroblasts, even under mitochondrial stress. We further tested whether a requirement for respirasomes emerges in vivo when OXPHOS biogenesis is progressively impaired through tissue-specific TFAM deletion. Respirasome depletion did not accelerate the loss of CI, CIII2 or CIV during disease progression. Together, our findings show that respirasomes are not a major determinant of post-assembly respiratory-chain complex maintenance, even when mitochondrial homeostasis and OXPHOS biogenesis are challenged.