Hypoxia rescues complex 1-associated disease caused by proteostatic defects.

Impaired mitochondrial proteostasis underlies a broad spectrum of diseases, yet effective therapies remain limited. Here we show that deficiency of HTRA2, a mitochondrial intermembrane space protease, can be rescued by hypoxia therapy. Using an Htra2 mutant mouse model that displays severe neurodegeneration and early lethality, we find that continuous hypoxia rescues striatal degeneration and extends lifespan. Mechanistically, we demonstrate that HTRA2 forms a functional complex with the disaggregase CLPB. Loss of function of either protein drives aggregation of intermembrane space-facing subunits of complex I of the electron transport chain, resulting in secondary complex I dysfunction. These changes impair tissue oxygen consumption and probably cause pathological hyperoxia, which is corrected by hypoxia. Together, these findings define a proteostasis pathway linking intermembrane space quality control to complex I function and expand the potential of hypoxia therapy to secondary complex I disease.