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Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.

  • Author(s): Wiley, Christopher D
  • Velarde, Michael C
  • Lecot, Pacome
  • Liu, Su
  • Sarnoski, Ethan A
  • Freund, Adam
  • Shirakawa, Kotaro
  • Lim, Hyung W
  • Davis, Sonnet S
  • Ramanathan, Arvind
  • Gerencser, Akos A
  • Verdin, Eric
  • Campisi, Judith
  • et al.
Abstract

Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.

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