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

2019 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7​
Mohanraj, K.; Wasilewski, M.; Benincá, C.; Cysewski, D.; Poznanski, J.; Sakowska, P. & Bugajska, Z. et al.​ (2019) 
EMBO Molecular Medicine11(5) art. e9561​.​ DOI: 

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Mohanraj, Karthik; Wasilewski, Michal; Benincá, Cristiane; Cysewski, Dominik; Poznanski, Jaroslaw; Sakowska, Paulina; Bugajska, Zaneta; Deckers, Markus; Dennerlein, Sven; Fernandez‐Vizarra, Erika; Rehling, Peter ; Dadlez, Michal; Zeviani, Massimo; Chacinska, Agnieszka
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 c 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.
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EMBO Molecular Medicine 
SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente 
SFB 1190 | P13: Protein Transport über den mitochondrialen Carrier Transportweg 
Working Group
RG Rehling (Mitochondrial Protein Biogenesis) 
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