ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium

ARTICLE: ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium AUTHORS: Mariam Meddeb, Navid Koleini, Mohammad Keykhaei, Ting Liu, Marcus Rhodehamel, Lorena Mandarano, Farnaz Farshidfar, Liang Zhao, Seoyoung Kwon, Gizem Keceli, Ismayil Ahmet, Nazareno Paolocci, Virginia Hahn, Kavita Sharma, Erika L Pearce, David A Kass JOURNAL: JACC Basic Transl Sci. 2025 Jul;10(7):101301. doi: 10.1016/j.jacbts.2025.04.015. Epub 2025 Jun 10. Abstract ATP-citrate lyase (ACLY) regulates lipogenesis and cell proliferation, and forms a cytosolic TCA-bypass circuit impacting NADH. We show that acute and chronic ACLY inhibition in cardiomyocytes depresses the NAD+/NADH ratio by increasing mitochondrial NADH. Acute suppression causes dose-dependent cytotoxicity, but at low doses augments aerobic respiration without impeding myocyte function. ACLY is reduced in human failing myocardium, and mice with myocardial or myocyte ACLY knockdown display mildly depressed function, particularly after pressure-overload, and exertional limitations. NAD+ enhancement ameliorates dysfunction/toxicity from ACLY inhibition. These results reveal that ACLY intrinsically regulates cardiac NAD+/NADH balance and respiration, which can affect rest and reserve heart function. For the full article, click here.