lncRNA Gm20257 alleviates pathological cardiac hypertrophy by modulating the PGC-1α–mitochondrial complex IV axis

Abstract

Pathological cardiac hypertrophy, a major contributor to heart failure, is closely linked to mitochondrial function. The roles of long noncoding RNAs (lncRNAs), which regulate mitochondrial function, remain largely unexplored in this context. Herein, a previously unknown lncRNA, Gm20257, was identified. It markedly increased under hypertrophic stress in vivo and in vitro. The suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte hypertrophy. Conversely, the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensin II–induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively, thus restoring cardiac function. Importantly, Gm20257 restored mitochondrial complex IV level and enhanced mitochondrial function. Bioinformatics prediction showed that Gm20257 had a high binding score with peroxisome proliferator–activated receptor coactivator-1 (PGC-1α), which could increase mitochondrial complex IV. Subsequently, Western blot analysis results revealed that Gm20257 substantially affected the expression of PGC-1α. Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that PGC-1α was a direct downstream target of Gm20257. This interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial ATP. These findings suggest that Gm20257 improves mitochondrial function through the PGC-1α–mitochondrial complex IV axis, offering a novel approach for attenuating pathological cardiac hypertrophy.

Keywords

lncRNA Gm20257 / cardiac hypertrophy / PGC-1α / mitochondrial complex IV / ATP

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Acknowledgements

This project was supported by the National Natural Science Foundation of China (Nos. 82170299 and 82003757), Major Projects of the National Natural Science Foundation of China (No. 82330011), the National Natural Science Foundation of China (No. 82370279), and the Postdoctoral Starting Fund of Heilongjiang Province (No. LBH-Q21121).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1065-7 and is accessible by authorized users.

Compliance with ethics guidelines

Conflicts of interest Tong Yu, Qiang Gao, Guofang Zhang, Tianyu Li, Xiaoshan Liu, Chao Li, Lan Zheng, Xiang Sun, Jianbo Wu, Huiying Cao, Fangfang Bi, Ruifeng Wang, Haihai Liang, Xuelian Li, Yuhong Zhou, Lifang Lv, and Hongli Shan declare that they have no conflicts of interest or financial conflicts to disclose.

All animal experiments followed the National Research Council’s Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of Harbin Medical University (No. HMUIRB-2020-04).

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