Cell Metabolism
Volume 23, Issue 2, 9 February 2016, Pages 303-314
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Article
Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

https://doi.org/10.1016/j.cmet.2015.11.011Get rights and content
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Highlights

  • Dysfunctional mitochondria cause cell senescence and a distinct secretory phenotype

  • This secretory phenotype can influence the differentiation of certain cell types

  • An NAD-AMPK-p53 pathway controls the secretory and mitotic arrest phenotypes

  • Mice with dysfunctional mitochondria and premature aging accumulate senescent cells

Summary

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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