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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 remodeling that underlies contractile decline and ultimately heart failure (HF). This narrative review focuses on the potential for therapeutic enhancement of TCA function by augmenting \u03b1-ketoglutarate (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 defense 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.<\/jats:p>","DOI":"10.1152\/ajpheart.00428.2026","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:32:31Z","timestamp":1790706751000},"page":"H1631-H1649","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Alpha-ketoglutarate dehydrogenase and citric acid cycle flexibility in heart disease and failure"],"prefix":"10.1152","volume":"331","author":[{"given":"Nadia","family":"Martinez Naya","sequence":"first","affiliation":[{"name":"University of Miami Leonard M. Miller School of Medicine","place":["United States"]},{"name":"University of Miami Leonard M. 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