title: Crosstalk between mitochondrial stress signals regulates yeast chronological lifespan.
abstract: Mitochondrial DNA (mtDNA) exists in multiple copies per cell and is essential for oxidative phosphorylation. Depleted or mutated mtDNA promotes numerous human diseases and may contribute to aging. Reduced TORC1 signaling in the budding yeast, Saccharomyces cerevisiae, extends chronological lifespan (CLS) in part by generating a mitochondrial ROS (mtROS) signal that epigenetically alters nuclear gene expression. To address the potential requirement for mtDNA maintenance in this response, we analyzed strains lacking the mitochondrial base-excision repair enzyme Ntg1p. Extension of CLS by mtROS signaling and reduced TORC1 activity, but not caloric restriction, was abrogated in ntg1Δ strains that exhibited mtDNA depletion without defects in respiration. The DNA damage response (DDR) kinase Rad53p, which transduces pro-longevity mtROS signals, is also activated in ntg1Δ strains. Restoring mtDNA copy number alleviated Rad53p activation and re-established CLS extension following mtROS signaling, indicating that Rad53p senses mtDNA depletion directly. Finally, DDR kinases regulate nucleus-mitochondria localization dynamics of Ntg1p. From these results, we conclude that the DDR pathway senses and may regulate Ntg1p-dependent mtDNA stability. Furthermore, Rad53p senses multiple mitochondrial stresses in a hierarchical manner to elicit specific physiological outcomes, exemplified by mtDNA depletion overriding the ability of Rad53p to transduce an adaptive mtROS longevity signal.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, United States; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schroeder
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, United States; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, United States. Electronic address: gerald.shadel@yale.edu.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
mesh_terms: D002453:Cell Cycle; D019069:Cell Respiration; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species; D012441:Saccharomyces cerevisiae / Q000378:metabolism / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C101825:NTG1 protein, S cerevisiae
keywords: Chronological lifespan; DNA damage response; Rad53p; Reactive oxygen species; mtDNA