TY - JOUR
T1 - Apoptotic stress causes mtDNA release during senescence and drives the SASP
AU - Victorelli, Stella
AU - Salmonowicz, Hanna
AU - Chapman, James
AU - Martini, Helene
AU - Vizioli, Maria Grazia
AU - Riley, Joel S.
AU - Cloix, Catherine
AU - Hall-Younger, Ella
AU - Machado Espindola-Netto, Jair
AU - Jurk, Diana
AU - Lagnado, Anthony B.
AU - Sales Gomez, Lilian
AU - Farr, Joshua N.
AU - Saul, Dominik
AU - Reed, Rebecca
AU - Kelly, George
AU - Eppard, Madeline
AU - Greaves, Laura C.
AU - Dou, Zhixun
AU - Pirius, Nicholas
AU - Szczepanowska, Karolina
AU - Porritt, Rebecca A.
AU - Huang, Huijie
AU - Huang, Timothy Y.
AU - Mann, Derek A.
AU - Masuda, Claudio Akio
AU - Khosla, Sundeep
AU - Dai, Haiming
AU - Kaufmann, Scott H.
AU - Zacharioudakis, Emmanouil
AU - Gavathiotis, Evripidis
AU - LeBrasseur, Nathan K.
AU - Lei, Xue
AU - Sainz, Alva G.
AU - Korolchuk, Viktor I.
AU - Adams, Peter D.
AU - Shadel, Gerald S.
AU - Tait, Stephen W.G.
AU - Passos, João F.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/10/19
Y1 - 2023/10/19
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-023-06621-4
DO - 10.1038/s41586-023-06621-4
M3 - Article
C2 - 37821702
AN - SCOPUS:85173867397
SN - 0028-0836
VL - 622
SP - 627
EP - 636
JO - Nature
JF - Nature
IS - 7983
ER -