title: Epigenetic silencing mediates mitochondria stress-induced longevity.
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.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schroeder
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Nuno
authors.initials: N
authors.lastname: Raimundo
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: gerald.shadel@yale.edu.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D057890:Epigenomics; D020868:Gene Silencing; D056466:Histone Demethylases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C400296:RPH1 protein, S cerevisiae; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; C084122:SIR3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D056466:Histone Demethylases; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; C513623:TEL1 protein, S cerevisiae; C067022:RAD53 protein, S cerevisiae