A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death

Article

关键词: ADENINE-NUCLEOTIDE TRANSLOCATOR;    CAP-INDEPENDENT TRANSLATION;    SACCHAROMYCES-CEREVISIAE;    PROTEOMIC ANALYSIS;    ISOBARIC TAGS;    LIFE-SPAN;    YEAST;    DISEASES;    COMPLEX;    DNA;   

DOI  :  10.1038/nature14859

来源: SCIE

【 摘 要 】

Mitochondria are multifunctional organelles whose dysfunction leads to neuromuscular degeneration and ageing. The multifunctionality 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, defects in iron-sulfur cluster biosynthesis, the release of pro-apoptotic and non-cell-autonomous signalling molecules, and altered stress signalling(1-5). Here we identify a new pathway of mitochondria-mediated cell death in yeast. This pathway was named mitochondrial precursor over-accumulation stress (mPOS), and is characterized by aberrant accumulation of mitochondrial precursors in the cytosol. mPOS can be triggered by clinically relevant mitochondrial damage that is not limited to the core machineries of protein import. We also discover a large network of genes that suppress mPOS, by modulating ribosomal biogenesis, messenger RNA decapping, transcript-specific translation, protein chaperoning and turnover. In response to mPOS, several ribosome-associated proteins were upregulated, 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 upregulation 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 association between these two hallmarks of degenerative diseases and ageing. The results are relevant to understanding diseases (for example, spinocerebellar ataxia, amyotrophic lateral sclerosis and myotonic dystrophy) that involve mutations within the anti-degenerative network.

【 授权许可】

Free