Mitochondrial metabolism and epigenetic crosstalk drive the SASP

  • Res Sq. 2024 Dec 5:rs.3.rs-5278203. doi: 10.21203/rs.3.rs-5278203/v1.
Joao Passos  1 ,  Helene Martini  1 ,  Jodie Birch  2 ,  Francisco Marques  3 ,  Stella Victorelli  1 ,  Anthony Lagnado  1 ,  Nicholas Pirius  1 ,  Ana Franco  1 ,  Gung Lee  1 ,  Yeaeun Han  1 ,  Jennifer Rowsey  1 ,  Alexandre Gaspar-Maia  1 ,  Aaron Havas  4 ,  Rabi Murad  5 ,  Xue Lei  6 ,  Rebecca Porritt  4 ,  Oliver Maddocks  7 ,  Diana Jurk  1 ,  Sundeep Khosla  1 ,  Peter Adams  4
Affiliations
  • 1. Mayo Clinic.
  • 2. MRC London Institute of Medical Sciences.
  • 3. Albert Einstein College of Medicine.
  • 4. Sanford Burnham Prebys Medical Discovery Institute.
  • 5. University of California, Irvine.
  • 6. Sanford Burnham Prebys MDI.
  • 7. Faeth Therapeutics.
PMID: 39678326 DOI: 10.21203/rs.3.rs-5278203/v1
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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