1. Apoptotic stress causes mtDNA release during senescence and drives the SASP.
- Author
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Victorelli S, Salmonowicz H, Chapman J, Martini H, Vizioli MG, Riley JS, Cloix C, Hall-Younger E, Machado Espindola-Netto J, Jurk D, Lagnado AB, Sales Gomez L, Farr JN, Saul D, Reed R, Kelly G, Eppard M, Greaves LC, Dou Z, Pirius N, Szczepanowska K, Porritt RA, Huang H, Huang TY, Mann DA, Masuda CA, Khosla S, Dai H, Kaufmann SH, Zacharioudakis E, Gavathiotis E, LeBrasseur NK, Lei X, Sainz AG, Korolchuk VI, Adams PD, Shadel GS, Tait SWG, and Passos JF
- Subjects
- Animals, Mice, Mitochondrial Transmembrane Permeability-Driven Necrosis, Proof of Concept Study, Inflammation metabolism, Phenotype, Longevity, Healthy Aging, Apoptosis, Cellular Senescence, Cytosol metabolism, DNA, Mitochondrial metabolism, Mitochondria genetics, Mitochondria metabolism
- 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., (© 2023. The Author(s).)- Published
- 2023
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