Metabolic-Epigenetic Coupling in Cellular Senescence: In Silico Cristae Remodeling Depletes Alpha-Ketoglutarate to Drive KDM4/6 Inhibition and SASP Amplification

Abstract

Cellular senescence is defined by stable cell-cycle withdrawal coupled with a hyper-secretory pro-inflammatory phenotype termed the senescence-associated secretory phenotype (SASP). While canonical paradigms emphasize persistent nuclear DNA damage response (DDR) signaling as the primary driver of the SASP, increasing evidence highlights autonomous organellar and metabolic checkpoints that perpetuate senescence independently of ongoing genomic genotoxicity. Here, we formulate a multi-scale in silico systems biology model integrating flux balance analysis, structural mitochondrial junction dynamics, and multi-cohort epigenomic regressions to characterize the causal link between mitochondrial cristae reorganization and chromatin remodeling in senescent human cells. Our simulations demonstrate that the progressive disassembly of the mitochondrial contact site and cristae organizing system (MICOS) complex, together with OPA1 cleavage, alters inner mitochondrial membrane topology, shifting cellular bioenergetics toward compensatory aerobic glycolysis. This architectural breakdown leads to a critical depletion of the mitochondrial and cytosolic alpha-ketoglutarate (alpha-KG) pool relative to the oncometabolites 2-hydroxyglutarate (2-HG) and succinate. Because alpha-KG serves as an indispensable obligate co-substrate for Jumonji C (JmjC) domain-containing histone demethylases, this metabolic shift competitively inhibits KDM4A/D (H3K9/H3K36 demethylases) and KDM6A/B (H3K27 demethylases). Kinetic docking and competitive inhibition modeling indicate a >70% loss of JmjC catalytic velocity, resulting in hypermethylation of activating histone marks (H3K4me3) and loss of repressive heterochromatin (H3K9me3/H3K27me3) across promoter regions of canonical SASP genes, including IL6, CXCL8, and MMP3. Transcriptomic cross-referencing across independent human senescent cohorts (GSE132442, GSE148074, GSE152011) validates this inverse metabolic-epigenetic correlation (R = −0.84, p < 1e-6). Finally, in silico anaplerotic supplementation using dimethyl-alpha-ketoglutarate (DM-AKG) or targeted succinate dehydrogenase modulation restores JmjC activity, re-establishes repressive chromatin architecture, and suppresses SASP hyper-transcription by >65%. These findings establish mitochondrial cristae topology and alpha-KG availability as an autonomous metabolic-epigenetic rheostat governing the chronic secretome of senescent cells and identify targeted anaplerosis as a viable therapeutic strategy to dampen senescent inflammation without impairing physiological cell-cycle arrest.