Apoptotic stress causes mtDNA release during senescence and drives the SASP

Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S. Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B. Lagnado, Lilian Sales Gomez, Joshua N. Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C. Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A. Porritt, Huijie Huang, Timothy Y. Huang, Derek A. Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H. Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K. LeBrasseur, Xue Lei, Alva G. Sainz, Viktor I. Korolchuk, Peter D. Adams, Gerald S. Shadel, Stephen W. G. Tait () and João F. Passos ()
Additional contact information
Stella Victorelli: Mayo Clinic
Hanna Salmonowicz: Mayo Clinic
James Chapman: Newcastle University
Helene Martini: Mayo Clinic
Maria Grazia Vizioli: Mayo Clinic
Joel S. Riley: Cancer Research UK Scotland Institute
Catherine Cloix: Cancer Research UK Scotland Institute
Ella Hall-Younger: Cancer Research UK Scotland Institute
Jair Machado Espindola-Netto: Mayo Clinic
Diana Jurk: Mayo Clinic
Anthony B. Lagnado: Mayo Clinic
Lilian Sales Gomez: Mayo Clinic
Joshua N. Farr: Mayo Clinic
Dominik Saul: Mayo Clinic
Rebecca Reed: Newcastle University
George Kelly: Newcastle University
Madeline Eppard: Mayo Clinic
Laura C. Greaves: Newcastle University
Zhixun Dou: Massachusetts General Hospital
Nicholas Pirius: Mayo Clinic
Karolina Szczepanowska: IMol Polish Academy of Sciences
Rebecca A. Porritt: Sanford Burnham Prebys Medical Discovery Institute
Huijie Huang: Sanford Burnham Prebys Medical Discovery Institute
Timothy Y. Huang: Sanford Burnham Prebys Medical Discovery Institute
Derek A. Mann: Newcastle University
Claudio Akio Masuda: Mayo Clinic
Sundeep Khosla: Mayo Clinic
Haiming Dai: Mayo Clinic
Scott H. Kaufmann: Mayo Clinic
Emmanouil Zacharioudakis: Albert Einstein College of Medicine
Evripidis Gavathiotis: Albert Einstein College of Medicine
Nathan K. LeBrasseur: Mayo Clinic
Xue Lei: Sanford Burnham Prebys Medical Discovery Institute
Alva G. Sainz: Salk Institute for Biological Studies
Viktor I. Korolchuk: Newcastle University
Peter D. Adams: Sanford Burnham Prebys Medical Discovery Institute
Gerald S. Shadel: Salk Institute for Biological Studies
Stephen W. G. Tait: Cancer Research UK Scotland Institute
João F. Passos: Mayo Clinic

Nature, 2023, vol. 622, issue 7983, 627-636

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06621-4

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