Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

Cell Metab. 2016 Feb 9;23(2):303-14. doi: 10.1016/j.cmet.2015.11.011. Epub 2015 Dec 10.

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.

Publication types

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

MeSH terms

  • Adenylate Kinase / metabolism
  • Animals
  • Cellular Senescence*
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase / metabolism
  • Enzyme Activation
  • Mice
  • Mitochondria / metabolism*
  • Mitochondria / pathology*
  • NAD / metabolism
  • Phenotype
  • Sirtuins / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Tumor Suppressor Protein p53
  • NAD
  • Adenylate Kinase
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • Polg protein, mouse
  • Sirtuins