Insertion Defects of Mitochondrially Encoded Proteins Burden the Mitochondrial Quality Control System

Abstract

The mitochondrial proteome contains proteins from two different genetic systems. Proteins are either synthesized in the cytosol and imported into the different compartments of the organelle or directly produced in the mitochondrial matrix. To ensure proteostasis, proteins are monitored by the mitochondrial quality control system, which will degrade non-native polypeptides. Defective mitochondrial membrane proteins are degraded by membrane-bound AAA-proteases. These proteases are regulated by factors promoting protein turnover or preventing their degradation. Here we determined genetic interactions between the mitoribosome receptors Mrx15 and Mba1 with the quality control system. We show that simultaneous absence of Mrx15 and the regulators of the i-AAA protease Mgr1 and Mgr3 provokes respiratory deficiency. Surprisingly, mutants lacking Mrx15 were more tolerant against proteotoxic stress. Furthermore, yeast cells became hypersensitive against proteotoxic stress upon deletion of MBA1. Contrary to Mrx15, Mba1 cooperates with the regulators of the m-AAA and i-AAA proteases. Taken together, these results suggest that membrane protein insertion and mitochondrial AAA-proteases are functionally coupled, possibly reflecting an early quality control step during mitochondrial protein synthesis.

Functional analyses of mitoribosome 54S subunit devoid of mitochondria‐specific protein sequences

“…To evaluate the quality of the mitochondrial translation process, we incubated the yeast cells in the presence of paromomycin. This aminoglycoside antibiotic is known to act on the mitoribosome, inducing translational misreading and proteotoxic stress in S. cerevisiae mitochondria (Suhm et al, 2018; Vargas Möller‐Hergt et al, 2018). All tested respiratory‐competent mutants showed an increased resistance of paromomycin compared to the wild‐type strain, with uL23‐23, bL31‐40, and bL19‐16, showing the higher rates of mitochondrial products accumulated compared to the untreated cells (Figure 10, top and bottom panels).…”

Overexpression of MRX9 impairs processing of RNAs encoding mitochondrial oxidative phosphorylation factors COB and COX1 in yeast

“…Paromomycin has been used to evaluate the quality of the mitochondrial translation process by inducing translational misreading and proteotoxic stress in S. cerevisiae mitochondria ( 50 , 51 ). The strain overexpressing MRX9 showed an increased resistance of paromomycin compared to the WT and the mrx9 null mutant strains ( Fig.…”

Collaborative subcellular compartmentalization to improve GPP utilization and boost sabinene accumulation in Saccharomyces cerevisiae

“…LSB3 responses to DNA damage which is another consequence of ROS accumulation brought by the cytotoxicity of monoterpenes [51]. MBA1 displays tolerance to mistranslation-induced proteotoxic stress [52]. And AIM25 also responses to oxidative stress.…”