Adaptations in Protein Expression and Regulated Activity of Pyruvate Dehydrogenase Multienzyme Complex in Human Systolic Heart Failure

Figure 1

Scheme of pyruvate dehydrogenase complex regulation. Pyruvate dehydrogenase (E1) performs decarboxylation of pyruvate and reductive acetylation of lipoic acid which binds dihydrolipoamide transacetylase (E2). E2 donates protons and electrons to the FAD of dihydrolipoamide dehydrogenase (E3) which converts dihydrolipoic acid and NAD+ into lipoic acid and NADH, reoxidizing E3. Phosphorylation of E1α by pyruvate dehydrogenase kinases (PDK1-4) inactivates E1 and subsequently the entire complex. Phosphorylation of the E1α subunit is reversed by pyruvate dehydrogenase phosphatase (PDP) and stimulated (via PDK regulation) by insulin, phosphoenolpyruvate, AMP, Ca²⁺, and Mg²⁺ and is competitively inhibited by ATP, NADH, and acetyl-coenzyme A (Acetyl-CoA). MPC1, MPC2 = mitochondrial pyruvate carrier heterodimer; DCA = dichloroacetate; FFA = free fatty acids; SIRT3 = sirtuin 3; FAD = flavin adenine dinucleotide; NAD = nicotinamide adenine dinucleotide; CoA-SH = coenzyme A.