Loss of ATP-Dependent Citrate Lyase Disrupts Cardiac Metabolism and Drives Left Ventricular Dysfunction
Heart failure remains a leading cause of morbidity and mortality worldwide, and metabolic dysregulation is a hallmark of the failing heart. Understanding the molecular switches that drive metabolic remodeling could open new therapeutic avenues. This study focuses on ATP-dependent citrate lyase (ACLY, also known as ACL), an enzyme that produces acetyl-CoA from citrate and supports de novo lipid synthesis. Although sustained glucose oxidation is observed during cardiac stress, the role of ACL in adapting to or maladapting to that stress has been unclear.
ACL abundance and activity are reduced in human hearts with nonischemic cardiomyopathy, correlating with lower levels of Krebs cycle intermediates.
Cardiac-specific loss of ACL in mice (via CRISPR/Cas9) decreases acetyl-CoA synthesis, increases glucose uptake and oxidation, impairs energy flux, and elevates the AMP/ATP ratio, leading to left ventricular dysfunction.
Compensatory pathways involve IDH1 (isocitrate dehydrogenase 1); deleting IDH1 in mouse hearts restores cardiac function and energy provision, suggesting a potential therapeutic strategy.
Metabolic stress from ACL loss activates AMPK and PKA, which inhibit YAP signaling through phosphorylation, linking metabolism to growth signaling.
Study Snapshot
Design: Translational study combining human tissue analysis, CRISPR/Cas9 gene editing in mice, multi-omics (RNA-seq, metabolomics, proteomics), stable isotope tracers, and computational metabolic network modeling (CardioNet).
Setting: Human heart tissue from healthy donors and patients with nonischemic cardiomyopathy (source provided by hospital biobank); mouse experiments in Myh6-Cas9 line.
Sample Size: Human samples (number not specified in abstract); mouse studies used gene-edited lines with appropriate controls.
Exposure: Loss of ACL enzyme (genetic inactivation of Acly in cardiomyocytes).
Comparator: Wild-type mice; healthy human donor tissue.
Primary Outcomes: Left ventricular function (assessed in vivo), metabolic flux (PET and tracer studies), multi-omics signatures, and downstream signaling (AMPK, PKA, YAP phosphorylation).
Key Findings: ACL loss reduces acetyl-CoA, disrupts cardiac energetics, and triggers compensatory IDH1-mediated citrate metabolism; AAV9-mediated Idh1 deletion improves function and reduces YAP phosphorylation.
Limitations: Human correlation data cannot confirm causation; mouse model may not fully replicate human HF; no clinical intervention tested yet.
How the Study Was Conducted
The research team, led by Liu, Karlstaedt, and colleagues, used a multi-pronged approach. First, they analyzed left ventricular tissue from healthy donors and patients with nonischemic cardiomyopathy to measure ACL protein abundance and enzyme activity, along with metabolite levels. They then introduced a cardiac-specific knockout of Acly in Myh6-Cas9 mice using CRISPR/Cas9 gene editing. In this mouse model, they performed in vivo positron emission tomography (PET) to assess glucose uptake and ex vivo stable isotope tracer labeling (using [¹³C]glucose and other tracers) to quantify metabolic fluxes. Multi-omics analysis included RNA sequencing for transcriptomics, mass spectrometry-based metabolomics and proteomics, and histone acetylation profiling. These experimental data were integrated into CardioNet, a computational model of cardiac metabolism, to identify system-level dysregulated pathways. The team also tested a potential rescue strategy by deleting Idh1 (encoding isocitrate dehydrogenase 1) via AAV9 delivery in the ACL-deficient mouse hearts.
What the Researchers Found
In human heart failure tissue, ACL protein abundance and enzymatic activity were significantly reduced, and this decrease correlated with lower levels of Krebs cycle intermediates, suggesting a bottleneck in citrate metabolism. In mice, cardiac-specific loss of ACL led to marked reduction in acetyl-CoA synthesis. The heart responded by increasing glucose uptake and oxidation, but energy flux became impaired, reflected by elevated AMP-to-ATP ratios. This metabolic stress activated AMP-activated protein kinase (AMPK) and protein kinase A (PKA), which in turn phosphorylated and inhibited the transcriptional coactivator YAP (Yes-associated protein), a key regulator of cardiac growth and function. Multi-omics data revealed compensatory lipid remodeling and reduced histone 3 acetylation. Stable isotope tracing and CardioNet simulations indicated that increased isocitrate dehydrogenase 1 (IDH1) activity prevents cytosolic citrate from accumulating, thereby avoiding allosteric inhibition of glycolysis. To test whether this IDH1 upregulation is adaptive or maladaptive, the researchers used AAV9 to delete Idh1 in ACL-deficient hearts. Remarkably, this restored cardiac function and energy provision, reduced YAP phosphorylation, and reactivated downstream YAP signaling.
CardioNet simulation reveals metabolic vulnerabilities in AclyKD
Mechanistic and Translational Insights
The study delineates a metabolic signaling cascade: ACL loss → reduced acetyl-CoA → energy stress → AMPK/PKA activation → YAP inhibition → left ventricular dysfunction. The compensatory role of IDH1 suggests that shunting citrate away from ACL and toward IDH1 may initially protect glycolysis but ultimately contributes to dysfunction by failing to support adequate ATP production. The rescue experiment with Idh1 deletion indicates that blocking this compensatory citrate flux can rebalance metabolism and improve function. This mechanism differs from previous models that focused solely on fatty acid oxidation or glucose oxidation; here, the citrate–acetyl-CoA axis emerges as a critical node. The multi-omics and computational modeling strengthen the translational relevance by linking human tissue observations to causal mouse genetics.
Strengths and Limitations
Strengths include the combination of human and mouse data, the use of state-of-the-art CRISPR editing to achieve cardiac-specific knockout, comprehensive multi-omics profiling, and computational modeling that integrates metabolic networks. The rescue experiment with Idh1 deletion provides a strong causal test of the compensatory pathway. However, limitations must be noted. The human data are correlational and derived from a single cardiomyopathy subtype (nonischemic); whether the findings apply to ischemic or other forms of heart failure is unknown. The mouse model, while powerful, may not fully recapitulate human heart failure pathophysiology, especially the chronic metabolic remodeling seen over years. No effect estimates (e.g., hazard ratios, P values) are reported in the abstract for key comparisons, making it impossible to assess statistical precision. The therapeutic intervention (AAV-mediated Idh1 deletion) has not been tested in humans, and potential off-target effects or long-term safety are not addressed. Residual confounding in the human tissue analysis (e.g., medication effects, comorbid conditions) cannot be excluded.
Implications for Practice and Research
This study identifies ACL as a pivotal regulator of cardiac metabolic adaptation and suggests that restoring acetyl-CoA synthesis or modulating citrate flux could be a therapeutic strategy for heart failure. The finding that deleting Idh1 improves function in mice opens a new line of investigation, but it is far from clinical readiness. Future studies need to validate these findings in larger human cohorts, assess the safety of IDH1 inhibition in chronic heart failure models, and determine whether patients with reduced ACL activity might benefit from metabolic interventions. For now, the work deepens understanding of how the heart's metabolic machinery influences growth signaling and function, and it highlights the potential of targeting central carbon metabolism beyond conventional substrates.
Funding, Disclosures, and Registration
The source article does not provide funding or disclosure information in the available abstract. No clinical trial registration is applicable for this translational study.
References
Liu S, Gammon ST, Tan L, et al. Loss of ATP-Dependent Citrate Lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling. Circulation. 2026;154(3):223-239. PMID: 42475434. https://pubmed.ncbi.nlm.nih.gov/42475434/
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.