Alpha-Ketoglutarate Dehydrogenase and Citric Acid Cycle Flexibility in Heart Disease and Failure

Tricarboxylic acid cycle (TCA) enzymes, mitochondrial isocitrate dehydrogenase (IDH2), α-ketoglutarate dehydrogenase (AKGDH), and succinyl-CoA synthetase (SCS) catalyse the conversion of isocitrate to succinate generating reducing equivalents for mitochondrial complex I and ATP by substrate level phosphorylation. Because of their central roles in energy metabolism, TCA enzymes and their metabolites distribute extensively across cellular compartments coordinating intermediary metabolism, cellular redox, and nuclear gene expression. AKGDH activity is regulated by acylation, oxidation, energy charge, substrates, and product succinyl-CoA. Global TCA dysfunction is both a consequence and cause of the adverse metabolic remodelling that underlies contractile decline and ultimately heart failure (HF). This narrative review focuses on the potential for therapeutic enhancement of TCA function by augmenting AKG and/or AKGDH in the settings of cardiovascular disease and HF. The results support significant reversibility of TCA dysfunction and multiple clinical contexts wherein AKG supplementation confers benefit by mechanisms that include enhanced antioxidant defence as well as anaplerosis with improved bioenergetics and segmental TCA flux despite coincident dysfunction of other TCA enzymes. Elevated systemic AKG, recently identified as a biomarker of HF, is associated with worse outcomes of heart disease and, in preclinical models, with hypertrophy, fibrosis, and neurotoxicity, such that the success of therapeutic manipulation may be critically determined by the disease stage and context.