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Peer-reviewedCC BYNature

Mitochondrial metabolism and epigenetic crosstalk drive SASP

  • Hélène Martini1,2
  • Jodie Birch3,4
  • Francisco Madeira Marques5
  • Stella G. Victorelli1,2
  • Anthony B. Lagnado1,2
  • Nicholas Pirius1,2
  • Ana Catarina Franco1,2
  • Gung Lee1,2
  • Yeaeun Han1,2
  • Jennifer L. Rowsey2
  • Wazim Mohammed Ismail6,7
  • Amelia Mazzone6,7
17 more authors
  • Tianna Espe8
  • Taro Hitosugi8
  • Ya Li9
  • Alexander M. Washington10,11
  • Aaron P. Havas12
  • Rabi Murad12
  • Xue Lei12
  • Rebecca A. Porritt12
  • Oliver D.K. Maddocks13
  • Jair Machado Espíndola‐Netto14
  • Dominik Saul15,16,2
  • Sundeep Khosla2
  • Diana Jurk1,2
  • Enis Kostallari17,10
  • Alexandre Gaspar‐Maia6,7
  • Peter D. Adams18
  • João F. Passos19,20
20 affiliations
  1. 1Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
  2. 2Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
  3. 3Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK
  4. 4MRC Laboratory of Medical Sciences (LMS), London, UK
  5. 5Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA
  6. 6Division of Experimental Pathology, Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  7. 7Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
  8. 8Department of Oncology, Division of Oncology Research, Mayo Clinic, Rochester, MN, USA
  9. 9Molecular Pharmacology and Experimental Therapeutics Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
  10. 10Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
  11. 11Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA
  12. 12Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
  13. 13School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK
  14. 14Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
  15. 15Eberhard Karls University Tuebingen, Tuebingen, Germany
  16. 16Robert Bosch Center for Tumor Diseases, Stuttgart, Germany
  17. 17Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
  18. 18Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. [email protected]
  19. 19Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA. [email protected]
  20. 20Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. [email protected]
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Abstract

Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.

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Cite

BibTeXRIS
BibTeX
@article{martini2026mitochondrial,
  title = {{Mitochondrial metabolism and epigenetic crosstalk drive SASP}},
  author = {Hélène Martini and Jodie Birch and Francisco Madeira Marques and Stella G. Victorelli and Anthony B. Lagnado and Nicholas Pirius and Ana Catarina Franco and Gung Lee and Yeaeun Han and Jennifer L. Rowsey and Wazim Mohammed Ismail and Amelia Mazzone and Tianna Espe and Taro Hitosugi and Ya Li and Alexander M. Washington and Aaron P. Havas and Rabi Murad and Xue Lei and Rebecca A. Porritt and Oliver D.K. Maddocks and Jair Machado Espíndola‐Netto and Dominik Saul and Sundeep Khosla and Diana Jurk and Enis Kostallari and Alexandre Gaspar‐Maia and Peter D. Adams and João F. Passos},
  journal = {Nature},
  year = {2026},
  month = jul,
  doi = {10.1038/s41586-026-10791-2},
  url = {https://doi.org/10.1038/s41586-026-10791-2},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Mitochondrial metabolism and epigenetic crosstalk drive SASP
AU  - Hélène Martini
AU  - Jodie Birch
AU  - Francisco Madeira Marques
AU  - Stella G. Victorelli
AU  - Anthony B. Lagnado
AU  - Nicholas Pirius
AU  - Ana Catarina Franco
AU  - Gung Lee
AU  - Yeaeun Han
AU  - Jennifer L. Rowsey
AU  - Wazim Mohammed Ismail
AU  - Amelia Mazzone
AU  - Tianna Espe
AU  - Taro Hitosugi
AU  - Ya Li
AU  - Alexander M. Washington
AU  - Aaron P. Havas
AU  - Rabi Murad
AU  - Xue Lei
AU  - Rebecca A. Porritt
AU  - Oliver D.K. Maddocks
AU  - Jair Machado Espíndola‐Netto
AU  - Dominik Saul
AU  - Sundeep Khosla
AU  - Diana Jurk
AU  - Enis Kostallari
AU  - Alexandre Gaspar‐Maia
AU  - Peter D. Adams
AU  - João F. Passos
PY  - 2026
DA  - 2026/07/29
JO  - Nature
DO  - 10.1038/s41586-026-10791-2
UR  - https://doi.org/10.1038/s41586-026-10791-2
AB  - Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.
SN  - 0028-0836
SN  - 1476-4687
ER  -