Proteasome activity contributes to pro-survival response upon mild mitochondrial stress in Caenorhabditis elegans

PLoS Biol. 2021 Jul 12;19(7):e3001302. doi: 10.1371/journal.pbio.3001302. eCollection 2021 Jul.

Abstract

Defects in mitochondrial function activate compensatory responses in the cell. Mitochondrial stress that is caused by unfolded proteins inside the organelle induces a transcriptional response (termed the "mitochondrial unfolded protein response" [UPRmt]) that is mediated by activating transcription factor associated with stress 1 (ATFS-1). The UPRmt increases mitochondrial protein quality control. Mitochondrial dysfunction frequently causes defects in the import of proteins, resulting in the accumulation of mitochondrial proteins outside the organelle. In yeast, cells respond to mistargeted mitochondrial proteins by increasing activity of the proteasome in the cytosol (termed the "unfolded protein response activated by mistargeting of proteins" [UPRam]). The presence and relevance of this response in higher eukaryotes is unclear. Here, we demonstrate that defects in mitochondrial protein import in Caenorhabditis elegans lead to proteasome activation and life span extension. Both proteasome activation and life span prolongation partially depend on ATFS-1, despite its lack of influence on proteasomal gene transcription. Importantly, life span prolongation depends on the fully assembled proteasome. Our data provide a link between mitochondrial dysfunction and proteasomal activity and demonstrate its direct relevance to mechanisms that promote longevity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / genetics
  • Enzyme Activation
  • Gene Knockdown Techniques
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Stress, Physiological*
  • Unfolded Protein Response

Substances

  • Caenorhabditis elegans Proteins
  • Mitochondrial Proteins
  • Proteasome Endopeptidase Complex

Grants and funding

The work was funded by the ‘Regenerative Mechanisms for Health’ project MAB/2017/2, performed within the International Research Agendas program of the Foundation for Polish Science, co-financed by the European Union under the European Regional Development Fund and the National Science Centre grant 2015/18/A/NZ1/00025 (AC group). In addition, MS was supported by an EMBO Short-Term Fellowship (7124). MT was supported by a POLONEZ Fellowship of National Science Centre, Poland, 2016/21/P/NZ3/03891, within European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 665778. UT was supported by National Science Centre grant 2015/19/B/NZ1/03444. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.