Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.

TitleInhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.
Publication TypeJournal Article
Year of Publication2019
AuthorsMohanraj, K, Wasilewski, M, Beninc√°, C, Cysewski, D, Poznanski, J, Sakowska, P, Bugajska, Z, Deckers, M, Dennerlein, S, Fernandez-Vizarra, E, Rehling, P, Dadlez, M, Zeviani, M, Chacinska, A
JournalEMBO Mol Med
Date Published2019 May

Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space (IMS) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein cytochrome oxidase assembly factor 7 (COA7), or RESpiratory chain Assembly 1 (RESA1) factor that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that COA7 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS We also found that pathogenic mutant versions of COA7 are imported slower than the wild-type protein, and mislocalized proteins are degraded in the cytosol by the proteasome. Interestingly, proteasome inhibition rescued both the mitochondrial localization of COA7 and complex IV activity in patient-derived fibroblasts. We propose proteasome inhibition as a novel therapeutic approach for a broad range of mitochondrial pathologies associated with the decreased levels of mitochondrial proteins.

Alternate JournalEMBO Mol Med
Citation Key10.15252/emmm.201809561
PubMed ID30885959
PubMed Central IDPMC6505684