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

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.

Author information

1
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
2
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA; SENS Research Foundation, 110 Pioneer Way, Mountain View, CA 94041, USA.
3
Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.
4
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA; Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Berkeley, CA 94720, USA. Electronic address: jcampisi@buckinstitute.org.

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.

PMID:
26686024
PMCID:
PMC4749409
DOI:
10.1016/j.cmet.2015.11.011
[Indexed for MEDLINE]
Free PMC Article

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