Cardiomyocyte-specific long noncoding RNA Trdn-as induces mitochondrial calcium overload by promoting the m⁶A modification of calsequestrin 2 in diabetic cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is a medical condition characterized by cardiac remodeling and dysfunction in individuals with diabetes mellitus. Sarcoplasmic reticulum (SR) and mitochondrial Ca²⁺ overload in cardiomyocytes have been recognized as biological hallmarks in DCM; however, the specific factors underlying these abnormalities remain largely unknown. In this study, we aimed to investigate the role of a cardiac-specific long noncoding RNA, D830005E20Rik (Trdn-as), in DCM. Our results revealed the remarkably upregulation of Trdn-as in the hearts of the DCM mice and cardiomyocytes treated with high glucose (HG). Knocking down Trdn-as in cardiac tissues significantly improved cardiac dysfunction and remodeling in the DCM mice. Conversely, Trdn-as overexpression resulted in cardiac damage resembling that observed in the DCM mice. At the cellular level, Trdn-as induced Ca²⁺ overload in the SR and mitochondria, leading to mitochondrial dysfunction. RNA-seq and bioinformatics analyses identified calsequestrin 2 (Casq2), a primary calcium-binding protein in the junctional SR, as a potential target of Trdn-as. Further investigations revealed that Trdn-as facilitated the recruitment of METTL14 to the Casq2 mRNA, thereby enhancing the m⁶A modification of Casq2. This modification increased the stability of Casq2 mRNA and subsequently led to increased protein expression. When Casq2 was knocked down, the promoting effects of Trdn-as on Ca²⁺ overload and mitochondrial damage were mitigated. These findings provide valuable insights into the pathogenesis of DCM and suggest Trdn-as as a potential therapeutic target for this condition.

Keywords

Trdn-as / calsequestrin 2 / METTL14 / mitochondrial dysfunction / calcium overload

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 82273919, 82270396, and U21A20339), the HMU Marshal Initiative Funding (No. HMUMIF-21022), and the Science Foundation for the Excellent Youth Scholars of Heilongjiang Province (No. JJ2023YX0509).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1102-6 and is accessible to authorized users.

Compliance with ethics guidelines

Conflicts of interest Xiaohan Li, Ling Liu, Han Lou, Xinxin Dong, Shengxin Hao, Zeqi Sun, Zijia Dou, Huimin Li, Wenjie Zhao, Xiuxiu Sun, and Xin Liu declare no competing interests. Baofeng Yang is one of Honorary Editors-in-Chief of Frontiers of Medicine. Yong Zhang is a member of the Editorial Board of Frontiers of Medicine. Baofeng Yang and Yong Zhang were excluded from the peer-review process and all editorial decisions related to the acceptance and publication of this article. Peer-review was handled independently by the other editors to minimise bias.

The use of animals has been approved by the Ethics Committee of Harbin Medical University (No. IRB3052724) and the protocols conformed to the Guidelines for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No.85-23, revised in 1996).

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