Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals

Abstract

Acetate is a major nutrient that supports acetyl-coenzymeA (Ac-CoA) metabolism and thus lipogenesis and protein acetylation. However, its source isunclear. 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 the context 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 denovo acetate production sustains Ac-CoA pools and cellproliferation in limited metabolic environments, such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. By virtue of denovo acetate production being coupled to mitochondrial metabolism, there are numerous possible regulatory mechanisms and links to pathophysiology.