title: Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.
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.
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Wiley
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Velarde
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Pacome
authors.initials: P
authors.lastname: Lecot
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA; SENS Research Foundation, 110 Pioneer Way, Mountain View, CA 94041, USA.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Sarnoski
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Freund
authors.affiliation: Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shirakawa
authors.affiliation: Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Hyung W
authors.initials: HW
authors.lastname: Lim
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Sonnet S
authors.initials: SS
authors.lastname: Davis
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Ramanathan
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Akos A
authors.initials: AA
authors.lastname: Gerencser
authors.affiliation: Gladstone Institutes, University of California San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.affiliation: 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.
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D016922:Cellular Senescence; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004789:Enzyme Activation; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D009243:NAD / Q000378:metabolism; D010641:Phenotype; D037761:Sirtuins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D009243:NAD; D000263:Adenylate Kinase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse; D037761:Sirtuins