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

Area of Science:

• Biochemistry
• Cardiology
• Metabolism

Background:

• ATP-citrate lyase (ACLY) is a key enzyme in lipogenesis and cell proliferation.
• ACLY participates in a cytosolic TCA-bypass circuit that influences NADH levels.
• The role of ACLY in cardiac metabolism and function is not fully understood.

Purpose of the Study:

• To investigate the impact of ATP-citrate lyase (ACLY) inhibition on cardiomyocyte metabolism and function.
• To determine the effect of ACLY on the NAD+/NADH ratio in the heart.
• To explore the therapeutic potential of NAD+ enhancement in conditions involving ACLY dysfunction.

Main Methods:

• Acute and chronic inhibition of ACLY in isolated cardiomyocytes and in vivo mouse models.
• Measurement of NAD+/NADH ratios and mitochondrial NADH levels.
• Assessment of cardiomyocyte cytotoxicity, aerobic respiration, and cardiac function under various conditions, including pressure overload.
• Evaluation of the effects of NAD+ enhancement on ACLY inhibition-induced dysfunction.

Main Results:

• ACLY inhibition in cardiomyocytes acutely depresses the NAD+/NADH ratio by increasing mitochondrial NADH.
• Low-dose acute ACLY suppression augments aerobic respiration without impairing myocyte function, while higher doses cause cytotoxicity.
• ACLY is downregulated in human failing myocardium.
• Myocardial or myocyte-specific ACLY knockdown in mice leads to mildly depressed cardiac function, especially under pressure overload, and exertional limitations.
• NAD+ enhancement mitigates the dysfunction and toxicity caused by ACLY inhibition.

Conclusions:

• ACLY intrinsically regulates cardiac NAD+/NADH balance and cellular respiration.
• Dysregulation of ACLY impacts both resting and reserve cardiac function.
• Targeting ACLY and NAD+ metabolism presents a potential therapeutic strategy for heart failure and related cardiac conditions.