Respiratory complex III₂ assembles complex I via toxic intermediate in mitochondrial disease.

ABSTRACT: Mutations in mitochondrial complex I can cause severe metabolic disease. Although no treatments are available for complex I deficiencies, chronic hypoxia improves lifespan and function in a mouse model of the severe mitochondrial disease Leigh syndrome caused by mutation of complex I subunit NDUFS4. To understand the molecular mechanism of NDUFS4 mutant pathophysiology and hypoxia rescue, we investigated the structure of complex I in respiratory supercomplexes isolated from NDUFS4 mutant mice. We identified complex I assembly intermediates bound to complex III₂, proving the cooperative assembly model. Further, an accumulated complex I intermediate is structurally consistent with pathological oxygen-dependent reverse electron transfer, revealing unanticipated pathophysiology and

SUBMITTER: Ayala-Hernandez MG 

PROVIDER: S-EPMC12262534 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature