Citrate metabolism and mitochondrial DNA signaling: cooperative regulation of the senescence-associated secretory phenotype

In a recent study published in Nature, Martini et al. demonstrate that mitochondrial citrate export supplies acetyl-CoA for histone acetylation at senescence-associated secretory phenotype (SASP) loci, thereby licensing the transcriptional response to mitochondrial DNA (mtDNA)-driven innate immune signaling. 1 Pharmacological inhibition of SLC25A1 suppresses SASP-associated chromatin accessibility and inflammation while preserving senescence-associated growth arrest, identifying a targetable metabolic–epigenetic checkpoint (Fig. 1 ). 1 Fig. 1 Full size image Mitochondrial citrate metabolism and mtDNA signaling converge to license SASP expression. a Minority mitochondrial permeabilization in senescent cells releases mtDNA into the cytosol, activating cGAS–STING signaling and downstream NF-κB/IRF3 inflammatory transcription factors. b Pyruvate import through MPC1/2 fuels mitochondrial citrate production; SLC25A1 exports citrate, which ACLY converts to nucleocytosolic acetyl-CoA. c Citrate-derived acetyl-CoA sustains H3K27ac and chromatin accessibility at SASP loci, enabling mtDNA-triggered transcription factors to drive robust SASP expression and cytokine secretion. d Pharmacological inhibition of SLC25A1 with CTPI2 reduces cytosolic acetyl-CoA and H3K27ac, suppressing SASP transcription without reversing senescence-associated growth arrest. e In aged mice, CTPI2 reduces SASP-associated inflammation and chromatin accessibility while preserving senescent-cell abundance, thereby delaying frailty and improving neuromuscular performance and skeletal muscle integrity. The figure was created by the authors using BioRender.com