2. Academic Validation
  3. FNDC4 Prevents Aging-Related Cardiac Dysfunction: By Restoring AMPKα/PPARα-Dependent Mitochondrial Function

FNDC4 Prevents Aging-Related Cardiac Dysfunction: By Restoring AMPKα/PPARα-Dependent Mitochondrial Function

  • JACC Basic Transl Sci. 2025 Jul;10(7):101222. doi: 10.1016/j.jacbts.2025.01.004.
Xin Zhang 1,  Wen-Sheng Dong 2,  Kang Li 2,  Yun-Jia Ye 2,  Can Hu 3
Affiliations

Affiliations

  • 1 Department of Geriatrics, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China. Electronic address: [email protected].
  • 2 Department of Geriatrics, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China.
  • 3 Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Research Center for Medical Imaging in Hubei Province, Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China. Electronic address: [email protected].
PMID: 40464727 DOI: 10.1016/j.jacbts.2025.01.004
Abstract

Mitochondria play critical roles in maintaining oxidative metabolism and cardiac homeostasis; however, their function is compromised in aging hearts. Fibronectin type III domain-containing 4 (FNDC4) is involved in regulating mitochondrial biogenesis, energy expenditure, and metabolic balance. The present study found that aging mice exhibited a sizable decline in cardiac and plasma FNDC4 levels, and that lower FNDC4 expression also correlated with a poor cardiac function. Cardiac-specific FNDC4 overexpression alleviated, while cardiac-specific FNDC4 knockdown facilitated aging-related cardiac remodeling and dysfunction. The unbiased transcriptome analysis and untargeted metabolomics revealed that FNDC4 activated AMP-activated protein kinase α/Peroxisome Proliferator-activated Receptor α signaling pathway to improve mitochondrial dysfunction and lipotoxicity in aging hearts.

Keywords

AMPKα; FNDC4; PPARα; cardiac aging; mitochondrial function.

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