Longevity & Aging

Mitochondrial Enzymes Moonlight in the Nucleus to Drive Gene Activation

Researchers discovered that two mitochondrial enzymes, aconitase 2 (ACO2) and isocitrate dehydrogenase 2 (IDH2), translocate to the nucleus where they run a reverse metabolic reaction — reductive carboxylation of alpha-ketoglutarate — to produce citrate and ultimately acetyl-CoA. This local acetyl-CoA fuels histone acetylation via the acetyltransferase KAT2A/GCN5, opening chromatin and activating proliferative gene programs. The pathway drives aggressive tumor behavior, suggesting the IDH2-ACO2-KAT2A axis represents a novel, targetable link between cellular metabolism and epigenetic gene control.