Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation

Science. 2012 Aug 3;337(6094):587-90. doi: 10.1126/science.1223560. Epub 2012 Jun 14.

Abstract

To better understand the response to mitochondrial dysfunction, we examined the mechanism by which ATFS-1 (activating transcription factor associated with stress-1) senses mitochondrial stress and communicates with the nucleus during the mitochondrial unfolded protein response (UPR(mt)) in Caenorhabditis elegans. We found that the key point of regulation is the mitochondrial import efficiency of ATFS-1. In addition to a nuclear localization sequence, ATFS-1 has an N-terminal mitochondrial targeting sequence that is essential for UPR(mt) repression. Normally, ATFS-1 is imported into mitochondria and degraded. However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus. Our results show that cells monitor mitochondrial import efficiency via ATFS-1 to coordinate the level of mitochondrial dysfunction with the protective transcriptional response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Nucleus / metabolism*
  • Gene Expression Regulation
  • Mitochondria / metabolism*
  • Nuclear Localization Signals / genetics
  • Nuclear Localization Signals / metabolism
  • Stress, Physiological*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Unfolded Protein Response*

Substances

  • ATFS-1 protein, C elegans
  • Caenorhabditis elegans Proteins
  • Nuclear Localization Signals
  • Transcription Factors

Associated data

  • GEO/GSE38196