Loss of ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling

Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. Methods: We utilized human heart tissue samples from healthy donor hearts and patients with non-ischemic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. Results: Here, we show that ACL expression is reduced in patients with reduced ejection fraction undergoing heart transplantation compared to healthy donors. In mice, loss of ACL increases glucose oxidation while reducing fatty acid oxidation to sustain contractile function. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that increased cytosolic citrate availability increases IDH1 protein abundance and flux. These compensatory metabolic alterations reduce histone 3 pan-acetylation and increase histone 3 lysine 4 methylation. Analysis of transcriptomic and protein data from heart tissue samples revealed downregulation of YAP and its target genes. Computational flux analysis and genome-scale metabolic modeling identified IDH1 as a therapeutic target to overcome the reduction of ACL. Conclusions: This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.