Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.

Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, Shirakawa K, Lim HW, Davis SS, Ramanathan A

Cell Metab 2016

1. 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. Wiley CD(1), Velarde MC(1), Lecot P(1), Liu S(1), Sarnoski EA(2), Freund A(1), Shirakawa K(3), Lim HW(3), Davis SS(1), Ramanathan A(1), Gerencser AA(1), Verdin E(3), Campisi J(4). 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. Comment in Cell Metab. 2016 Feb 9;23(2):229-30. doi: 10.1016/j.cmet.2016.01.012. Trends Biochem Sci. 2016 Mar;41(3):207-209. doi: 10.1016/j.tibs.2016.01.005. 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. Copyright © 2016 Elsevier Inc. All rights reserved. DOI: 10.1016/j.cmet.2015.11.011 PMCID: PMC4749409 PMID: 26686024 [Indexed for MEDLINE] Conflict of interest statement: The other authors declare no conflicts of interest.