Pck1 Deficiency Drives Mitochondrial Dysfunction and Cellular Senescence in Adipocytes.

Cellular senescence of white adipose tissues (WAT) represents an early hallmark of aging; however, the involved mechanisms remain incompletely understood. Here, we identified the cytosolic phosphoenolpyruvate carboxykinase (Pck1) as a key regulator of mitochondrial function and inflammaging in WAT. Pck1 expression was downregulated in both gonadal WAT and inguinal WAT during aging, and adipocyte-specific Pck1 deficiency accelerated inflammaging and metabolic disorders. Untargeted metabolomic and isotope-tracing analyses revealed that loss of Pck1 impaired cataplerosis, the export of tricarboxylic acid (TCA) cycle intermediates, resulting in accumulation of fumarate in adipocytes. Supplementation with exogenous fumarate disrupted mitochondrial homeostasis of adipocytes, promoted oxidative stress and triggered cytosolic release of mitochondrial DNA (mtDNA), leading to the activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway that may contribute to inflammaging and chronic obesity. These were phenocopied with Pck1-deficient adipocytes. Conversely, overexpression of fumarate hydratase (Fh1) reduced fumarate level substantially and attenuated adipocyte inflammaging. Collectively, these findings identify Pck1 as a pivotal regulator of mitochondrial metabolic homeostasis and suggest that targeting Pck1 may represent a promising therapeutic strategy for age-related diseases.