Epigenetic silencing mediates mitochondria stress-induced longevity

Cell Metab. 2013 Jun 4;17(6):954-964. doi: 10.1016/j.cmet.2013.04.003.

Abstract

Reactive oxygen species (ROS) play complex roles in aging, having both damaging effects and signaling functions. Transiently elevating mitochondrial stress, including mitochondrial ROS (mtROS), elicits beneficial responses that extend lifespan. However, these adaptive, longevity-signaling pathways remain poorly understood. We show here that Tel1p and Rad53p, homologs of the mammalian DNA damage response kinases ATM and Chk2, mediate a hormetic mtROS longevity signal that extends yeast chronological lifespan. This pathway senses mtROS in a manner distinct from the nuclear DNA damage response and ultimately imparts longevity by inactivating the histone demethylase Rph1p specifically at subtelomeric heterochromatin, enhancing binding of the silencing protein Sir3p, and repressing subtelomeric transcription. These results demonstrate the existence of conserved mitochondria-to-nucleus stress-signaling pathways that regulate aging through epigenetic modulation of nuclear gene expression.

Publication types

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

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Checkpoint Kinase 2 / genetics
  • Checkpoint Kinase 2 / metabolism*
  • DNA Damage
  • DNA Repair / genetics*
  • Epigenomics
  • Gene Silencing
  • Histone Demethylases / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Longevity / genetics*
  • Longevity / physiology
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Reactive Oxygen Species / metabolism
  • Repressor Proteins / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction / genetics
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / metabolism

Substances

  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • RPH1 protein, S cerevisiae
  • Reactive Oxygen Species
  • Repressor Proteins
  • SIR3 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae
  • Histone Demethylases
  • Checkpoint Kinase 2
  • Protein-Serine-Threonine Kinases
  • TEL1 protein, S cerevisiae
  • RAD53 protein, S cerevisiae

Associated data

  • GEO/GSE45383