Mitochondrial Translation Efficiency Controls Cytoplasmic Protein Homeostasis

• Published in: Cell metabolism 2018-06, Vol.27 (6), p.1309-1322.e6
• Main Authors: Suhm, Tamara, Kaimal, Jayasankar Mohanakrishnan, Dawitz, Hannah, Peselj, Carlotta, Masser, Anna E., Hanzén, Sarah, Ambrožič, Matevž, Smialowska, Agata, Björck, Markus L., Brzezinski, Peter, Nyström, Thomas, Büttner, Sabrina, Andréasson, Claes, Ott, Martin
• Format: Article
• Language: English
• Subjects: activation; aggregate handling; aging; Biochemistry; biokemi; Cell Biology; Cell Nucleus - metabolism; Cellbiologi; chronological life-span; DNA-Binding Proteins - metabolism; Endocrinology & Metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; Gene Expression Regulation; gene-expression; mechanism; misfolded proteins; Mitochondria - genetics; Mitochondria - metabolism; mitochondria-to-nucleus communication; mitochondrial protein synthesis; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; mitochondrial ribosome; Mitochondrial Ribosomes - metabolism; Molecular Bioscience; molekylär biovetenskap; OXPHOS; Phosphatidylinositol 3-Kinases - metabolism; Protein Biosynthesis; protein folding; Proteostasis - genetics; quality-control; Reactive Oxygen Species - metabolism; ribosome; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; saccharomyces-cerevisiae; shock transcription factor; Signal Transduction; stress signaling; TOR1 signaling; Transcription Factors - metabolism; translational fidelity; yeast
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2018.04.011

Cellular proteostasis is maintained via the coordinated synthesis, maintenance, and breakdown of proteins in the cytosol and organelles. While biogenesis of the mitochondrial membrane complexes that execute oxidative phosphorylation depends on cytoplasmic translation, it is unknown how translation within mitochondria impacts cytoplasmic proteostasis and nuclear gene expression. Here we have analyzed the effects of mutations in the highly conserved accuracy center of the yeast mitoribosome. Decreased accuracy of mitochondrial translation shortened chronological lifespan, impaired management of cytosolic protein aggregates, and elicited a general transcriptional stress response. In striking contrast, increased accuracy extended lifespan, improved cytosolic aggregate clearance, and suppressed a normally stress-induced, Msn2/4-dependent interorganellar proteostasis transcription program (IPTP) that regulates genes important for mitochondrial proteostasis. Collectively, the data demonstrate that cytosolic protein homeostasis and nuclear stress signaling are controlled by mitochondrial translation efficiency in an inter-connected organelle quality control network that determines cellular lifespan. [Display omitted] •Changes in mitochondrial translation accuracy reciprocally affect stress resistance•Msn2/4 regulate a transcription program for mitochondrial proteostasis during aging•Organellar proteostasis cooperates with TOR1-dependent signaling in shaping aging•Mitochondrial translation modulates cytoplasmic protein quality control systems Suhm et al. show that mitochondrial protein translation impacts cytoplasmic proteostasis and nuclear gene expression. By analyzing mutations in the highly conserved mitochondrial ribosome, they show that mitochondrial translation accuracy is linked to cytoplasmic proteostasis, ROS, and a novel interorganellar proteostasis transcription program (IPTP), impacting chronological lifespan.