PotM - August 2026

Mitochondrial metabolism and epigenetic crosstalk drive SASP

Martini, H. et al., Nature 2026

Brief Summary

How do mitochondria drive inflammation in senescent cells?

In a new study published in Nature, led by João Passos and Peter Adams, with Helene Martini as first author, the team uncovered a metabolic-epigenetic pathway controlling the senescence-associated secretory phenotype (SASP).

Previous work by the Passos Lab showed that senescent mitochondria release mtDNA into the cytosol, activating cGAS-STING and inflammatory signaling. This new study shows that mitochondria also provide citrate to generate acetyl-CoA, promoting histone acetylation and increased chromatin accessibility at SASP genes.

Inhibiting SLC25A1, the mitochondrial citrate transporter, suppresses the SASP without affecting cytosolic mtDNA, showing that distinct mitochondrial pathways converge to regulate inflammation. Importantly, targeting mitochondrial citrate transport in aged mice reduced chromatin accessibility at SASP genes, decreased age-associated inflammation and improved healthspan.

Together, the study reveals how mitochondrial signaling, metabolism and epigenetic regulation converge to sustain inflammation in senescent cells during aging.

Interview to the corresponding authors Prof. Peter D. Adams (Sanford Burnham Prebys) & João F. Passos (Mayo Clinic)

What is the potential impact of this work?

João Passos

Peter Adams

By identifying mitochondrial citrate metabolism as a key regulator of the inflammatory phenotype of senescent cells, this work reveals a new way to target the detrimental effects of cellular senescence without eliminating senescent cells themselves. This could open new therapeutic strategies to reduce age-related inflammation and diseases driven by senescent cell accumulation.

What question does this paper open for the future?

Does mitochondrial citrate metabolism play different roles in acute, physiological senescence versus the persistent senescence that develops during aging?

What does ICSA represent to you, and how does this paper connect with the ICSA community?

ICSA brings together a diverse community working to understand cellular senescence, from its fundamental mechanisms to its role in aging and disease and its therapeutic potential. This paper reflects that breadth by uncovering how mitochondrial metabolism and epigenetic regulation shape the inflammatory phenotype of senescent cells. By linking fundamental mechanisms of cellular senescence to interventions that reduce age-related inflammation and improve healthspan, the study closely reflects the ICSA community.