2. Academic Validation
  3. ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium

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

  • JACC Basic Transl Sci. 2025 Jun 10;10(7):101301. doi: 10.1016/j.jacbts.2025.04.015.
Mariam Meddeb 1,  Navid Koleini 1,  Mohammad Keykhaei 1,  Ting Liu 1,  Marcus Rhodehamel 1,  Lorena Mandarano 1,  Farnaz Farshidfar 1,  Liang Zhao 2,  Seoyoung Kwon 1,  Gizem Keceli 1,  Ismayil Ahmet 3,  Nazareno Paolocci 1,  Virginia Hahn 1,  Kavita Sharma 1,  Erika L Pearce 4,  David A Kass 5
Affiliations

Affiliations

  • 1 Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 2 Complete Omics Inc, Halethorpe, Baltimore, Maryland, USA.
  • 3 Laboratory of Cardiovascular Sciences, National Institute of Aging, Baltimore, Maryland, USA.
  • 4 Department of Oncology, Department of Biochemistry and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 5 Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, Maryland, USA. Electronic address: dkass@jhmi.edu.
PMID: 40499285 DOI: 10.1016/j.jacbts.2025.04.015
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.

Keywords

TCA cycle; heart disease; metabolism; myocardium; redox; reductive stress.

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