Prohibitin 2 deficiency impairs cardiac fatty acid oxidation and causes heart failure

Dechao Wu,Ling Zhao,Xianhua Wang,Heping Cheng,Tingting Hou,Qi Peng,Yanru Wang,Chongshu Jian,Chuan-Yun Li,Keling Wu,Wen Zheng,Bizhi Shang,Qi Ma,Minglei Zhao

doi:10.1038/s41419-020-2374-7

Dechao Wu, Ling Zhao + Show 12 more

Open Access

https://doi.org/10.1038/s41419-020-2374-7

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Abstract

Fatty acids are the most major substrate source for adult cardiac energy generation. Prohibitin 2 (PHB2), a highly conserved protein located in mitochondrial inner membrane, plays key roles in cellular energy metabolic homeostasis. However, its functions in regulating cardiac fatty acid metabolism have remained largely unknown. Our study demonstrates that cardiac-specific knockout of Phb2 leads to accumulation of lipid droplets and causes heart failure. Mechanistically, ablation of PHB2 impairs cardiac fatty acid oxidation (FAO) through downregulating carnitine palmitoyltransferase1b (CPT1b), a rate-limiting enzyme of cardiac mitochondrial FAO. Moreover, overexpression of CPT1b alleviates impaired FAO in PHB2-deficient cardiomyocytes. Thus, our study provides direct evidence for the link between PHB2 and cardiac fatty acid metabolism. Our study points out that PHB2 is a potential FAO regulator in cardiac mitochondrial inner membrane, as well as the connection between PHB2 and CPT1b and their relationships to cardiac pathology especially to cardiac fatty acid metabolic disorder.

Highlights

Despite decades of research, heart failure is still a leading cause of morbidity and mortality in modern society[1]
Cardiac echocardiography (ECHO) measurements demonstrated cardiac systolic dysfunctions in Phb[2] cKO mice at 8 weeks of age (Fig. 1e), showing both ejection fraction (EF) and fractional shortening (FS) diminished by 70% compared with wild type (WT) (Fig. 1f)
Prohibitin 2 (PHB2) deficiency causes heart failure and lethality in mice Heart failure is one of the leading causes of death worldwide, which is characterized by perturbations in energy production and lack of adequate oxygen supply for maintaining proper heart contractility[36]

Summary

Introduction

Heart failure is still a leading cause of morbidity and mortality in modern society[1]. It is a complex clinical syndrome, in which abnormality in cardiac pump function leads to inadequate oxygen supply and perturbed energy metabolism for maintaining normal requirement of cardiac contractility[2]. A variety of mechanisms have been involved in the pathogenesis of heart failure, including metabolic disorder, mitochondrial dysfunction, autophagy, apoptosis, and genetic or epigenetic dysregulation[3,4,5]. A high rate of ATP production and turnover is required for maintaining normal cardiac functions[2]. The function of cardiac PHB2 is less well known, especially in fatty acid metabolic regulation

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