Soluble adenylyl cyclase regulates the cytosolic NADH/NAD+ redox state and the bioenergetic switch between glycolysis and oxidative phosphorylation

The evolutionarily conserved soluble adenylyl cyclase (sAC, ADCY10 ) mediates cAMP signaling exclusively in intracellular compartments. Because sAC activity is sensitive to local concentrations of ATP, bicarbonate, and free Ca 2+ , potentially an important metabolic sensor. Nonetheless, little known about how regulates energy metabolism intact cells. In this study, we demonstrated that both pharmacological genetic suppression resulted increased lactate secretion decreased pyruvate multiple cell lines primary cultures mouse hepatocytes cholangiocytes. extracellular lactate-to-pyruvate ratio upon reflected cytosolic [NADH]/[NAD + ] ratio, which was corroborated by using the NADH/NAD redox biosensor Peredox-mCherry. Mechanistic studies permeabilized HepG2 cells showed inhibition specifically suppressed complex I mitochondrial respiratory chain. A survey effectors revealed only selective exchange protein activated 1 (Epac1), but not kinase (PKA) or Epac2, I-dependent respiration significantly state. Analysis ATP production rate adenylate charge inhibiting reciprocally affects glycolysis oxidative phosphorylation while maintaining cellular homeostasis. conclusion, our study shows that, via regulation respiration, sAC-Epac1 state, coordinates maintain As such, effectively a bioenergetic switch between aerobic at post-translational level. • phosphorylation, glycolysis. controls for Suppression acutely induces mechanism. state Epac1.