Cardiomyocyte-specific long noncoding RNA Trdn-as induces mitochondrial calcium overload by promoting the m6A modification of calsequestrin 2 in diabetic cardiomyopathy.
10.1007/s11684-024-1102-6
- Author:
Xiaohan LI
1
;
Ling LIU
1
;
Han LOU
1
;
Xinxin DONG
1
;
Shengxin HAO
1
;
Zeqi SUN
1
;
Zijia DOU
1
;
Huimin LI
1
;
Wenjie ZHAO
1
;
Xiuxiu SUN
1
;
Xin LIU
1
;
Yong ZHANG
2
;
Baofeng YANG
3
Author Information
1. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin, 150081, China.
2. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin, 150081, China. zy@ems.hrbmu.edu.cn.
3. Department of Pharmacology (SKLFZCD, State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin, 150081, China. yangbf@ems.hrbmu.edu.cn.
- Publication Type:Journal Article
- Keywords:
Trdn-as;
METTL14;
calcium overload;
calsequestrin 2;
mitochondrial dysfunction
- MeSH:
Animals;
Diabetic Cardiomyopathies/pathology*;
RNA, Long Noncoding/genetics*;
Myocytes, Cardiac/metabolism*;
Mice;
Calsequestrin/genetics*;
Calcium/metabolism*;
Male;
Sarcoplasmic Reticulum/metabolism*;
Methyltransferases/metabolism*;
Mice, Inbred C57BL;
Mitochondria, Heart/metabolism*;
Disease Models, Animal;
Mitochondria/metabolism*
- From:
Frontiers of Medicine
2025;19(2):329-346
- CountryChina
- Language:English
-
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.
