BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy

Ermin Li,Qianqian Liang,Ruizhe Qian,Ning Sun,Chen Xu,Xiuya Li,Jie Huang,Aobing Bai,Kehan Ren,Chao Lu

doi:10.1007/s13238-020-00713-x

Abstract

Dysregulation of circadian rhythms associates with cardiovascular disorders. It is known that deletion of the core circadian gene Bmal1 in mice causes dilated cardiomyopathy. However, the biological rhythm regulation system in mouse is very different from that of humans. Whether BMAL1 plays a role in regulating human heart function remains unclear. Here we generated a BMAL1 knockout human embryonic stem cell (hESC) model and further derived human BMAL1 deficient cardiomyocytes. We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function. We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression. BMAL1 knockout directly reduced BNIP3 protein level, causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function. Our data indicated that the core circadian gene BMAL1 is critical for normal mitochondria activities and cardiac function. Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.

Highlights

The circadian clock, known as a circadian oscillator, is ubiquitously present in every cell and critical to regulate internal physiological rhythms and behaviors throughout an organism’s life
We show that brain and musle ARNT-like 1 (BMAL1) deficient human embryonic stem cells (hESCs)-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments
Mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function

Summary

Introduction

The circadian clock, known as a circadian oscillator, is ubiquitously present in every cell and critical to regulate internal physiological rhythms and behaviors throughout an organism’s life. The body’s circadian clock produces a robust 24-hour rhythmic activity as the Earth rotates (Kang et al, 2009). These intrinsic circadian rhythms are based on transcriptional-translational feedback loops (TTFLs) to maintain organ homeostasis (Dierickx et al, 2018). Global Bmal1-deficient mice displayed age-associated dilated cardiomyopathy (DCM), exhibiting left ventricular dilatation and contractile dysfunction (Lefta et al, 2012). This suggests that dysregulation of circadian rhythms may cause gradual abnormality of heart function and lead to cardiac dilation and failure. The molecular mechanisms of BMAL1 deficiency leading to the DCM phenotype is unclear

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Results

Conclusion