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

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 ( COA 7), or RES piratory chain Assembly 1 ( RESA 1) factor that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that COA 7 requires the mitochondrial IMS import and assembly ( MIA ) pathway for efficient accumulation in the IMS . We also found that pathogenic mutant versions of COA 7 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 COA 7 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.

Cytosolic translational responses differ under conditions of severe short-term and long-term mitochondrial stress

“…For further investigation of cytosolic translational responses under conditions of long-term mitochondrial stress, we silenced MIA40 for 72 h. The oxidoreductase MIA40 is responsible for the import of proteins into the intermembrane space of mitochondria (Chacinska et al , 2004). MIA40 also plays an important role in the biogenesis of respiratory chain complex enzymes in mitochondria (Longen et al , 2009; Mohanraj et al , 2019). The knockdown of MIA40 had an effect similar to that of treating the cells with menadione or rotenone for 48 h, but in HeLa cells, protein synthesis and expression of ATF4 were decreased (Figure 6, C and D; Supplemental Figure 6, A and B); however, ROS production and ATP levels were not significantly changed (Figure 6, A and B).…”

Improved Supra-Organization Is A Conformational And Functional Adaptation Of Respiratory Complexes

“…Endoplasmic Reticulum stress has been reported to stimulate SC-formation (Balsa et al, 2019). Proteasome inhibition protects RC-assembly factor COA7 from degradation and improves CIV function in models of mitochondrial leukoencephalopathy (Mohanraj et al, 2019). Our data also suggests that triggering iSRC by mild proteostasis stress may offer an opportunity to ameliorate OxPhos-deficiency in mitochondrial diseases.…”

Stop wasting protein—Proteasome inhibition to target diseases linked to mitochondrial import

“…COA7 variants were not completely impaired in IMS import and folding, but their import and folding was strongly slowed down. Preventing cytosolic degradation via pharmacological inhibition of the proteasome thus not only increased cellular COA7 mutant levels, but also enabled mitochondrial import of COA7 variants, and restored complex IV activity and supercomplex formation (Mohanraj et al , ; Fig ).…”

“…In the current issue of EMBO Molecular Medicine, Mohanraj et al (2019) identified cytochrome c oxidase assembly factor 7 (COA7) as a novel non-conventional disulfide relay substrate. Cytochrome c oxidase assembly factor 7 is involved in the assembly of complex IV (Kozjak-Pavlovic et al, 2014).…”