ATP-Citrate Lyase in Heart Failure

Heart failure (HF) is a syndrome characterized by high morbidity and mortality, clinically categorized as heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF). Though distinct in contractile performance and hemodynamic profiles, both phenotypes share fundamental perturbations in cardiac intermediary metabolism and mitochondrial redox balance.¹ Traditionally, redox imbalance in HF has been attributed to oxidative stress²; however, emerging evidence highlights reductive stress, defined by excessive NADH accumulation and impaired NAD⁺ regeneration, as a central contributor to mitochondrial dysfunction and metabolic inflexibility.³ This redox imbalance compromises mitochondrial respiration and impairs NAD⁺-dependent enzymatic activity, limiting metabolic flexibility and disrupting excitation–contraction coupling, thereby contributing to contractile dysfunction, hypertrophy, and fibrosis.⁴

Beyond its canonical role in redox reactions, NAD⁺ acts as a cosubstrate for enzymatic systems governing transcriptional regulation, calcium handling, and DNA repair, including sirtuins (NAD⁺-dependent deacetylases), PARP1 [poly(ADP-ribose) polymerase 1], and CD38 (a major NAD⁺ hydrolase), thereby linking NAD⁺ availability to broader cellular adaptations under metabolic stress.⁵ Deficits in NAD⁺ regeneration promote mitochondrial protein hyperacetylation, perturb redox-sensitive shuttle systems such as the malate-aspartate pathway, and sensitize the permeability transition pore, compromising cardiac mitochondrial integrity and energetics.⁶ In preclinical models of both HFrEF and HFpEF, NAD⁺ precursor supplementation improves cardiac energetics and performance, underscoring redox imbalance as a shared therapeutic target.⁷ However, the upstream metabolic processes that affect cytosolic-mitochondrial NAD⁺/NADH homeostasis in the failing heart remain incompletely understood.

In this issue of JACC: Basic to Translational Science, Meddeb et al⁸ identify the cytosolic enzyme ATP-citrate lyase (ACLY) as a previously under-recognized regulator of myocardial redox balance. ACLY converts mitochondrial citrate and coenzyme A into acetyl-CoA and oxaloacetate (OAA), enabling cytosolic acetyl-CoA generation for lipid synthesis and histone/protein acetylation, while OAA can be recycled to malate and returned to the mitochondria. This pathway acts as a cytosolic bypass of the tricarboxylic acid (TCA) cycle, diverting intermediates away from NADH-generating mitochondrial dehydrogenases (eg, isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase) (Figure 1).⁹ In proliferative cells such as cancer, ACLY activity supports anabolic growth by enabling both acetyl-CoA generation and NADH depletion.⁹ Meddeb et al now demonstrate that this bypass is operative in postmitotic cardiac myocytes, in which it limits mitochondrial NADH accumulation, supporting redox homeostasis and cardiac function.

Figure 1.

ACLY Supports Redox Balance and Cardiac Function

In the normal heart (left), ATP-citrate lyase (ACLY) catalyzes the conversion of citrate into acetyl-CoA and oxaloacetate (OAA) in the cytosol. OAA is reduced to malate and recycled into mitochondria, facilitating cytosolic NAD⁺ regeneration and limiting mitochondrial NADH buildup. This redox bypass sustains mitochondrial redox balance, metabolic flexibility, and contractile reserve. In heart failure (right), ACLY downregulation impairs this bypass, leading to citrate accumulation, reduced malate recycling, and elevated mitochondrial NADH. The resulting reductive stress contributes to energetic imbalance, impaired mitochondrial adaptation, and diminished systolic function. NAD⁺ supplementation may partially restore redox homeostasis. ADP = adenosine diphosphate; ATP = adenosine triphosphate.

Using pharmacological inhibition (BMS-303141) and genetic knockdown models, the authors demonstrate that ACLY actively limits mitochondrial NADH accumulation in cardiomyocytes by shunting citrate away from full TCA cycle oxidation. Disruption of this function via ACLY inhibition or silencing acutely lowered the NAD⁺/NADH ratio due to excessive mitochondrial NADH accumulation and modestly increased oxygen consumption rate. Despite no immediate change in contractile performance, dose-dependent cytotoxicity occurred at higher inhibitor concentrations, attributable not to oxidative stress but to reductive stress-induced mitochondrial dysfunction, as previously implicated in HF pathogenesis. These findings are reinforced by in vivo data: cardiac-specific ACLY knockdown in mice caused subtle declines in systolic function, which worsened under pressure overload and were rescued by NAD⁺ precursor supplementation, mirroring preclinical therapeutic outcomes in HF models.³

Importantly, Meddeb et al⁸ show that ACLY expression is significantly reduced in failing human hearts from patients with both HFpEF and HFrEF. In preclinical models, cardiomyocyte-specific ACLY suppression lowered the myocardial NAD⁺/NADH ratio and impaired cardiac stress adaptation, suggesting that the observed reduction in human heart failure may contribute to reductive stress and diminished metabolic plasticity. Accumulation of mitochondrial NADH under these conditions may inhibit NAD⁺-sensitive TCA cycle enzymes, such as citrate synthase and isocitrate dehydrogenase, thereby exacerbating metabolic inflexibility. During elevated energetic demand, reduced cytosolic NAD⁺ availability may further constrain NAD⁺-dependent adaptive pathways involved in maintaining mitochondrial function (eg. sirtuin-mediated deacetylation or PARP1 activity). Although ACLY suppression transiently increased mitochondrial respiration, the mismatch between NADH accumulation and NAD⁺ regeneration highlights a bottleneck in NADH/NAD⁺ redox cycling and mitochondrial adaptive capacity under stress.

Taken together, these findings position ACLY not merely as a biosynthetic enzyme, but as a central integrator of myocardial redox regulation and metabolic plasticity. ACLY’s influence on the NAD⁺/NADH ratio bridges mitochondrial bioenergetics with redox-dependent signaling pathways and cardiac contractile function. In fact, ACLY also governs nutrient sensing and metabolic substrate switching in other cell types (eg. immune and cancer cells), underscoring its broader regulatory role within intermediary metabolism. This integrative function becomes critical under hemodynamic stress, in which ACLY fine-tunes the cytosolic-mitochondrial redox crosstalk, directly coupling redox balance to myocardial metabolic plasticity and mitochondrial adaptive capacity. These insights are timely, as both NAD⁺-boosting strategies and ACLY inhibitors advance toward clinical application, emphasizing the need for mechanistically guided evaluation of their cardiac impact.

Several aspects of the study warrant careful consideration. For instance, while the acute effects of ACLY inhibition on NADH and respiration were clearly demonstrated, the longer-term consequences for mitochondrial biogenesis, protein acetylation, and sirtuin-mediated deacetylation remain to be defined, a gap underscored by the unresolved mechanism linking NADH accumulation to cytotoxicity without reactive oxygen species (ROS) elevation. Given ACLY’s dual role in acetyl-CoA production and NADH buffering, its suppression may exert pleiotropic effects on chromatin regulation and epigenetic adaptability. Moreover, although BMS-303141 has been used in clinical settings, its limited specificity at higher concentrations (as noted in prior studies) remains a concern. The authors strengthen their conclusions through genetic models, yet off-target effects in chronic pharmacological inhibition (eg. mitochondrial or TCA cycle enzyme interactions) cannot be fully excluded. Interestingly, despite substantial NADH accumulation, ROS levels did not increase, challenging conventional redox paradigms and supporting a dissociation between reductive stress and oxidative damage. This finding may in part reflect a compensatory upregulation of antioxidative capacity (eg. glutathione or thioredoxin systems) but is also consistent with the concept of redox-optimized ROS balance, which proposes that mitochondrial ROS emission is determined by the interaction between the redox environment and respiratory flux, rather than by redox potential alone.¹⁰ The present findings further extend this framework by integrating nodes of intermediary metabolism such as ACLY and TCA cycle control. This conceptual expansion is timely, particularly given the consistent downregulation of ACLY observed in both HFpEF and HFrEF human myocardium. The functional relevance of this suppression is supported by the concordant NAD⁺/NADH imbalance in genetic models, highlighting its pathophysiological significance in HF.

Future studies should dissect how ACLY-mediated NAD⁺/NADH modulation impacts cardiomyocyte viability and adaptation under energetic stress. This includes elucidating whether the observed cytotoxicity stems from impaired NAD⁺-dependent signaling, metabolic inflexibility, or maladaptive excitation–contraction coupling. Integrating ACLY's redox function with mitochondrial respiration, chromatin regulation, and stress-responsive signaling will be essential to understand its role in cardiac resilience. Given the clinical development of ACLY inhibitors for cancer and dyslipidemia, these findings underscore the need to evaluate potential cardiac off-target effects, particularly under physiologic stressors such as pressure overload or exercise that challenge myocardial reserve. Meddeb et al⁸ reposition ACLY from a metabolic enzyme to a central node in myocardial redox regulation. By linking ACLY-dependent NAD⁺/NADH balance to mitochondrial and functional adaptation, their study refines current models of metabolic failure and opens new translational avenues for targeting redox balance in cardiomyopathy.

Funding Support and Author Disclosures

Dr Maack is funded by the DFG (SFB-1525/project No. 453989101 and Ma: 2528/8-1) and the German Center for Cardiovascular Research (DZHK; EX-22 and FKZ 81X2800227); and is an advisory board member or speaker for Amgen, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Edwards, Lilly, Novartis, NovoNordisk, and Servier. Mr Weissman has reported that he has no relationships relevant to the contents of this paper to disclose.