• Home
  • Search Results
  • Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.

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

EMBO molecular medicine (2019-03-20)
Karthik Mohanraj, Michal Wasilewski, Cristiane Benincá, Dominik Cysewski, Jaroslaw Poznanski, Paulina Sakowska, Zaneta Bugajska, Markus Deckers, Sven Dennerlein, Erika Fernandez-Vizarra, Peter Rehling, Michal Dadlez, Massimo Zeviani, Agnieszka Chacinska
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
Sigma-Aldrich
GeneJuice® Transfection Reagent, Non-lipid based chemical transfection reagent optimized for maximum transfection efficiency, ease-of-use, and minimal cytotoxicity on a wide variety of mammallian cells.
Sigma-Aldrich
Diamide
Sigma-Aldrich
Anti-COA7 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution, ab2
Sigma-Aldrich
Anti-Smac antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-COA7 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution, ab1
Sigma-Aldrich
Anti-UQCRC1 antibody produced in rabbit, Ab1, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Monoclonal Anti-Heat Shock Protein 60 antibody produced in mouse, clone LK1, ascites fluid