Apoptotic stress causes mtDNA release during senescence and drives the SASP

Victorelli, S. et al. (2023) Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature, 622(7983), pp. 627-636. (doi: 10.1038/s41586-023-06621-4) (PMID:37821702) (PMCID:PMC10584674)

Abstract

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.

• Item Type: Articles
• Additional Information: This work was funded by NIH grants R01AG068048 (JFP); UG3CA268103 (JFP); P01 AG062413 (SK, JNF, NKL, JFP), P01 AG073084 and R01 AR069876 (GSS), F31 AG062099 (AGS), R01 AG068182-01 (DJ), R01 CA225996 (SHK and HD), R01 DK128552 (JNF), R01 AG071861-01 (XL, PDA), P01 AG073084 (PDA, XL), R01 AG076515 (SK), R01 AG061875 and RF1 AG070391 (TYH), R01AG071861 (PDA), Department of Defense grant W81XWH-20-1-0792 (EG), U54 AG79754 (SK, NKL), Cancer Research UK grants C40872/A2014, DRCNPG-Jun22\100011 (S.W.G.T), the Ted Nash long life foundation (JFP, DJ), The Glenn Foundation For Medical Research (JFP, NKL), Hevolution/AFAR (DJ), a Robert and Arlene Kogod Center on Aging Career Development Award (SGV), 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 (CAM). BBSRC PhD studentship BB/R506345/1 (GK, VIK). CRUK Awards C18342/A23390 and DRCRPG-Nov22/100007, and MRC MR/R023026/1 (DAM). GSS holds the Audrey Geisel Chair in Biomedical Science. MS interactome analysis was done 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 (KS).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tait, Professor Stephen and Adams, Professor Peter and Cloix, Dr Catherine and Hall-Younger, Ella and Mann, Professor Derek and Riley, Dr Joel and Vizioli, Dr Maria Grazia
• Authors: Victorelli, S., Salmonowicz, H., Chapman, J., Martini, H., Vizioli, M. G., Riley, J. S., Cloix, C., Hall-Younger, E., Espindola-Netto, J. M., Jurk, D., Lagnado, A. B., Gomez, L. S., Farr, J. N., Saul, D., Reed, R., Kelly, G., Eppard, M., Greaves, L. C., Dou, Z., Pirius, N., Szczepanowska, K., Porritt, R. A., Huang, H., Huang, T. Y., Mann, D. A., Masuda, C. A., Khosla, S., Dai, H., Kaufmann, S. H., Zacharioudakis, E., Gavathiotis, E., LeBrasseur, N. K., Lei, X., Sainz, A. G., Korolchuk, V. I., Adams, P. D., Shadel, G. S., Tait, S. W.G., and Passos, J. F.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature
• Publisher: Nature Research
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 11 October 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Nature 622(7983):627–636
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
313511		The role of sub-lethal mitochondrial apoptotic stress in cellular senescence	Stephen Tait	National Institute on Aging (NATIAGIN)	1R01AG068048-01	SCS - Beatson Institute for Cancer Research
172007		Apoptosis as an oncogenic process: understanding and exploiting its dark-side	Stephen Tait	Cancer Research UK (CRUK)	C40872/A20145	School of Cancer Sciences
316271		Understanding and targeting cell death oncogenicity	Stephen Tait	Cancer Research UK (CRUK)	DRCNPG-Jun22\100011	SCS - Therapeutic Science Research