Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals

Acetate is a major nutrient that supports acetyl-coenzyme A (Ac-CoA) metabolism and thus lipogenesis and protein acetylation. Its source however has been unclear. Here we report that pyruvate, the end product of glycolysis and key node in central carbon metabolism, quantitatively generates acetate in mammals. This phenomenon becomes more pronounced in contexts of nutritional excess such as during hyperactive glucose metabolism. Conversion of pyruvate to acetate occurs through two mechanisms: 1) coupling to reactive oxygen species (ROS), and 2) neomorphic enzyme activity from keto acid dehydrogenases that enable function as pyruvate decarboxylases. Further, we demonstrate that de novo acetate production sustains Ac-CoA pools and cell proliferation in limited metabolic environments such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. De novo acetate production occurs in mammals and is further coupled to mitochondrial metabolism providing possible regulatory mechanisms and links to pathophysiology.