Apoptotic stress causes mtDNA release during senescence and drives the SASP

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS–STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
This work was funded by NIH grants R01AG068048 (to J.F.P.), UG3CA268103 (to J.F.P.), P01 AG062413 (to S.K., J.N.F., N.K.L. and J.F.P.), P01 AG073084 and R01 AR069876 (to G.S.S.), F31 AG062099 (to A.G.S.), R01 AG068182-01 (to D.J.), R01 CA225996 (to S.H.K. and H.D.), R01 DK128552 (to J.N.F.), R01 AG071861-01 (to X.L. and P.D.A.), P01 AG073084 (to P.D.A. and X.L.), R01 AG076515 (to S.K.), U54 AG079754 (to S.K.), R01 AG061875 and RF1 AG070391 (to T.Y.H.), R01AG071861 (to P.D.A.) and R33AG61456-4 and R01AG064165; Department of Defense grant W81XWH-20-1-0792 (to E.G.); U54 AG79754 (to S.K. and N.K.L.); Cancer Research UK grants C40872/A2014, DRCNPG-Jun22\100011 (to S.W.G.T.); the Ted Nash Long Life Foundation (to J.F.P. and D.J.); The Glenn Foundation For Medical Research (to J.F.P. and N.K.L.); Hevolution/AFAR (to D.J.); a Robert and Arlene Kogod Center on Aging Career Development Award (to S.V.); a fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (Capes)—Finance Code 001 and by the Universidade Federal do Rio de Janeiro (to C.A.M.); Cancer Research UK grant DRCPFA-Nov22/100001 and Wellcome grant 203105/Z/16/Z0 to L.C.G., BBSRC PhD studentship BB/R506345/1 (to G.K. and V.I.K.); UKRI cross-council Newcastle University Centre for Ageing and Vitality Ph.D. studentship MR/L016354/1 (to J.C.) and CRUK Awards C18342/A23390 and DRCRPG-Nov22/100007 and MRC MR/R023026/1 (to D.A.M.). G.S.S. holds the Audrey Geisel Chair in Biomedical Science. MS interactome analysis was performed at the Proteomic Core Facility of IMol Polish Academy of Sciences and supported by ReMedy International Research Agenda (Foundation of Polish Science, MAB/2017/2) and EMBO Installation Grant 5040-2022 (to K.S.). scRNA-seq was performed by the Sanford Burnham Prebys Genomics Core. G.S.S. holds the Audrey Geisel Chair in Biomedical Science and is supported by P30AG068635 as director of the San Diego Nathan Shock Center. We thank G. Nelson and the members of the Newcastle U