Key result
ACLY inhibition depresses cardiac function and alters respiration, especially after pressure overload.
Why the study?
Does ACLY inhibition alter NAD+/NADH balance and cardiac function in cardiomyocytes and mouse models?
Does ACLY inhibition alter NAD+/NADH balance and cardiac function in cardiomyocytes and mouse models?
ACLY plays a critical role in maintaining cardiac NAD+/NADH balance and respiration, and its reduction in failing myocardium may contribute to cardiac dysfunction.
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.
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Meddeb et al. (2025) studied Heart failure. ACLY inhibition or knockdown vs. Control (uninhibited/wild-type) was evaluated on Cardiac function and NAD+/NADH balance. ACLY inhibition in cardiomyocytes and mice depresses the NAD+/NADH ratio and mildly depresses cardiac function, particularly after pressure-overload, revealing its role in regulating cardiac respiration.
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