A Cytosolic Network Suppressing Mitochondria-Mediated Proteostatic Stress and Cell Death

Mitochondria are multifunctional organelles whose dysfunction leads to neuromuscular degeneration and ageing. The multi-functionality poses a great challenge for understanding the mechanisms by which mitochondrial dysfunction causes specific pathologies. Among the leading mitochondrial mediators of cell death are energy depletion, free radical production, defect in iron-sulfur cluster biosynthesis, the release of pro-apoptotic and non-cell-autonomous signaling molecules, and altered stress signaling (1–5). Here, we identified a novel pathway of mitochondria-mediated cell death. This pathway was named mitochondrial Precursor Over-accumulation Stress (mPOS), characterized by aberrant accumulation of mitochondrial precursors in the cytosol. mPOS can be triggered by clinically relevant mitochondrial damage which is not limited to the core machineries of protein import. We also identified a large network of genes that suppress mPOS, by modulating ribosomal biogenesis, mRNA decapping, transcript-specific translation, protein chaperoning and turnover. In response to mPOS, several ribosome-associated proteins were up-regulated including Gis2 and Nog2, which promote cap-independent translation and inhibit the nuclear export of the 60S ribosomal subunit respectively (6, 7). Gis2 and Nog2 up-regulation promotes cell survival, which may be part of a feedback loop that attenuates mPOS. Our data indicate that mitochondrial dysfunction contributes directly to cytosolic proteostatic stress, and provide an explanation for the enigmatic association between these two hallmarks of degenerative diseases and ageing. The results are relevant to understanding diseases (e.g., spinocerebellar ataxia, amyotrophic lateral sclerosis and myotonic dystrophy) that involve mutations within the anti-degenerative network.