Key result
Acox2 deficiency drives heart failure in mice via widespread loss of cardiac protein succinylation.
Why the study?
Pathogenic mechanisms of secondary cardiomyopathies such as cirrhotic cardiomyopathy remain poorly understood due to a lack of optimal experimental models.
Does Acox2 deficiency induce cardiac dysfunction via cross-organ metabolic reprogramming in mice?
Does Acox2 deficiency induce cardiac dysfunction via cross-organ metabolic reprogramming in mice?
Acox2 deficiency in mice leads to cardiac dysfunction driven by cross-organ metabolic signaling and reduced protein succinylation, offering insights into the pathogenesis of secondary cardiomyopathies such as cirrhotic cardiomyopathy.
Acox2 deficiency links metabolic signaling to HF in mice; hypothesis-generating for succinylation in human secondary cardiomyopathies, needs patient validation.
Background Secondary cardiomyopathies are a major cause of heart failure (HF) with diverse etiologies and high mortality rates. For example, over 50% of patients with end-stage liver disease develop cardiac dysfunction, clinically termed cirrhotic cardiomyopathy (CCM). While serum metabolites mediating cross-organ communication are known to play a critical role in CCM development, the underlying pathogenic mechanisms remain poorly understood due to a lack of optimal experimental models. Methods We generated Acox2 knockout (KO) mice using CRISPR/Cas9 technology to investigate the role of ACOX2, a rate-limiting peroxisomal enzyme. Cardiac function was assessed via echocardiography. We performed RNA sequencing and quantitative proteomic analyses to evaluate cardiac gene expression. Furthermore, global succinylome profiling was conducted to determine changes in protein succinylation, and global metabolomics analysis was used to identify significantly differentially expressed metabolites (SDMs). Results Acox2 KO mice successfully recapitulated the hepatic phenotypes observed in patients with ACOX2 homozygous mutations, including liver fibrosis and lymphocytic infiltration. Given that ACOX2 is not expressed in the mouse heart throughout its lifespan, we initially hypothesized that Acox2 deficiency would have no direct impact on cardiac function. However, by 6 months of age, Acox2 KO mice exhibited significantly compromised cardiac parameters via echocardiography, alongside elevated biomarkers of cardiomyopathy and heart failure. While Acox2 deficiency had limited impact on the cardiac proteome, global succinylome profiling revealed a pervasive decrease in protein succinylation in Acox2 KO hearts. Notably, approximately 60% of these hypo-succinylated sites were located on mitochondrial and myofibrillar proteins, including SUCLA2 (K94), CS (K321), FH (K470), MDH1 (K110), OGDH (K999), TNNC1 (K86), VCL (K453), MYH7 (K83), and MYL3 (K9)—a profile tightly associated with cardiomyopathy. Seahorse assays and scanning electron microscopy further indicated impaired mitochondrial function in Acox2 KO mice. Metabolomic analysis revealed a dramatic accumulation of plasma C27 bile acid intermediates and a concomitant decrease in cardiac succinyl-CoA levels. Conclusions Our findings underscore the critical role of the succinylation landscape in maintaining cardiac function. The cardiac pathology observed in Acox2 KO mice originates from cross-organ metabolic signaling, providing new insights into the pathogenesis of secondary cardiomyopathies, such as cirrhotic cardiomyopathy.
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A 2026 study studied Secondary cardiomyopathy. Acox2 knockout vs. Wild-type littermates was evaluated on Cardiac function and protein succinylation. Acox2 deficiency in mice induced cardiac dysfunction and heart failure by 6 months of age, driven by a pervasive decrease in cardiac protein succinylation originating from cross-organ metabolic signaling.
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