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Cell Metab. 2018 Jun 5;27(6):1309-1322.e6. doi: 10.1016/j.cmet.2018.04.011. Epub 2018 May 10.

Mitochondrial Translation Efficiency Controls Cytoplasmic Protein Homeostasis.

Author information

1
Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
2
Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
3
Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-413 90 Göteborg, Sweden.
4
Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden; National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, SE-17165 Solna, Sweden.
5
Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden; Institute of Molecular Biosciences, NAWI Graz, University of Graz, A-8010 Graz, Austria.
6
Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden. Electronic address: claes.andreasson@su.se.
7
Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden. Electronic address: martin.ott@dbb.su.se.

Abstract

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.

KEYWORDS:

OXPHOS; TOR1 signaling; aggregate handling; aging; mitochondria-to-nucleus communication; mitochondrial protein synthesis; mitochondrial ribosome; protein folding; stress signaling; translational fidelity

PMID:
29754951
DOI:
10.1016/j.cmet.2018.04.011

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