MassIVE MSV000101385

Partial Public PXD076639

HYPOXIA RESCUES COMPLEX 1-ASSOCIATED DISEASE CAUSED BY DEFECTS IN THE HTRA2-CLPB PROTEOSTASIS SYSTEM

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Description

Impaired mitochondrial proteostasis underlies a broad spectrum of diseases, yet effective therapies remain limited. Our prior CRISPR screens nominated more than 75 disease genes whose deficiency could be rescued by hypoxia therapy, including HTRA2, a mitochondrial intermembrane space protease. Here, we validated this concept in an Htra2 mutant mouse model that displays severe neurodegeneration and early lethality, closely mirroring human disease. Continuous hypoxia rescued striatal degeneration and extended lifespan. Mechanistically, we found that HTRA2 forms a functional complex with the disaggregase CLPB. Loss of either protein's function drives aggregation of intermembrane space-facing subunits of ETC Complex 1 (C1), resulting in secondary C1 dysfunction. This impairs tissue oxygen consumption and likely causes pathological hyperoxia, which is corrected by hypoxia. Together, these findings define a proteostasis pathway linking intermembrane space quality control to C1 function and expand the potential of hypoxia therapy to secondary C1 disease [doi:10.25345/C5K931M2G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: HTRA2, Hypoxia, Proteostasis, CLPB, Complex 1 ; DatasetType:Proteomics

Contact

Principal Investigators:
(in alphabetical order) 		Isha Jain, Gladstone Institutes, USA
Submitting User: agarg2
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