Mitochondrial metabolism and epigenetic crosstalk drive the SASP.

Joao Passos, Helene Martini, Jodie Birch, Francisco Marques, Stella Victorelli, Anthony Lagnado, Nicholas Pirius, Ana Franco, Gung Lee, Yeaeun Han, Jennifer Rowsey, Alexandre Gaspar-Maia, Aaron Havas, Rabi Murad, Xue Lei, Rebecca Porritt, Oliver Maddocks, Diana Jurk, Sundeep Khosla, Peter Adams

Mayo Clinic.Mayo Clinic. · pubmed

Paper

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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Research summary

The paper addresses the role of mitochondrial metabolism in the regulation of the senescence-associated secretory phenotype (SASP), which is directly linked to aging and age-related inflammation. By identifying potential therapeutic targets that could mitigate the effects of senescent cells, the research contributes to understanding the underlying mechanisms of aging. However, while the findings are significant, they represent an important but not groundbreaking advance in the field, hence the moderate impact score.

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