FGF21-FGFR1 controls mitochondrial homeostasis in cardiomyocytes by modulating the degradation of OPA1

Abstract Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone, secreted mainly by the liver, considered as a major regulator of energy homeostasis. Recent research revealed that FGF21 could play an important role in cardiac pathological remodeling effects and preventing cardiomyopathy, but the underlying mechanism remained largely unknown. The aim of this study was to clarify the mechanism of FGF21 cardiac protective effects. We engineered FGF21 knock out mice, and the effects of FGF21 and its downstream mediators were subsequently elucidated using western blot, qRT-PCR, and mitochondrial morphological, functional analysis. FGF21 knock out mice resulted in cardiac dysfunction accompanied by a decline in global longitudinal strain (GLS) and ejection fraction (EF) which was independently of obesity. Mitochondrial quality, quantity and functions were abnormal accompanied with the decreased levels of optic atrophy-1 (OPA1) in FGF21 KO mice. In contrast to FGF21 knockdown, the cardiac specific overexpression of FGF21 can alleviate cardiac dysfunction caused by FGF21 deficiency. In vitro study FGF21 siRNA can deteriorate mitochondrial dynamics, functions impairment induced by CoCl2. Both recombinant FGF21 and adeno virus mediated FGF21 overexpression can alleviate CoCl2 induced mitochondrial impairment by restoring mitochondrial dynamics. FGF21 is essential for maintaining mitochondrial dynamics and functions in cardiomyocytes. FGF21, as an important target in regulating cardiomyocytes mitochondrial homeostasis under oxidative stress, will provide new therapeutic options for heart failure patients.