Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation

Fan Yu, Jingsi Duan, Zhengyin Lou, Guo-Ping Shi, Fuzhe Gong, Lingfeng Zhong, Derong Chen, Li Xu, Tingting Hong, Xinyang Hu, Jinghai Chen, Jian’an Wang () and Deling Yin ()
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Fan Yu: Zhejiang University School of Medicine
Jingsi Duan: Zhejiang University School of Medicine
Zhengyin Lou: Zhejiang University School of Medicine
Guo-Ping Shi: Harvard Medical School
Fuzhe Gong: Zhejiang University School of Medicine
Lingfeng Zhong: Zhejiang University School of Medicine
Derong Chen: Zhejiang University School of Medicine
Li Xu: Zhejiang University School of Medicine
Tingting Hong: Zhejiang University School of Medicine
Xinyang Hu: Zhejiang University School of Medicine
Jinghai Chen: Zhejiang University School of Medicine
Jian’an Wang: Zhejiang University School of Medicine
Deling Yin: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Myocardial energy metabolism disorders are essential pathophysiology in sepsis-associated myocardial injury. Yet, the underlying mechanisms involving impaired mitochondrial respiratory function upon myocardial injury remain poorly understood. Here we identify an unannotated and cardiomyocyte-enriched long non-coding RNA, Cpat (cardiac-protector-associated transcript), that plays an important role in regulating the dynamics of cardiomyocyte mitochondrial tricarboxylic acid (TCA) cycle. Cpat is essential to the mitochondrial respiratory function by targeting key metabolic enzymes and modulating TCA cycle flux. Specifically, Cpat enhances the association of TCA cycle core components malate dehydrogenase (MDH2), citrate synthase (CS), and aconitase (ACO2). Acetyltransferase general control non-repressed protein-5 (GCN5) acetylates CS and destabilizes the MDH2-CS-ACO2 complex formation. Cpat inhibits this GCN5 activity and facilitates MDH2-CS-ACO2 complex formation and TCA cycle flux. We reveal that Cpat-mediated mitochondrial metabolic homeostasis is vital in mitigating myocardial injury in sepsis-induced cardiomyopathy, positioning Cpat as a promising therapeutic target for preserving myocardial cellular metabolism and function.

Date: 2025
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DOI: 10.1038/s41467-025-64072-z

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