BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the developme
- PDF / 7,645,620 Bytes
- 19 Pages / 595.276 x 785.197 pts Page_size
- 85 Downloads / 197 Views
Protein & Cell
RESEARCH ARTICLE BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy ,
1
Department of Physiology and Pathophysiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China 2 Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China 3 Shanghai Key Lab of Birth Defect, Children’s Hospital of Fudan University, Shanghai 201102, China 4 Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai 200032, China 5 Research Center on Aging and Medicine, Fudan University, Shanghai 200032, China & Correspondence: [email protected] (C. Lu), [email protected] (R. Qian), [email protected] (N. Sun) Received November 3, 2019 Accepted March 18, 2020
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 Ermin Li, Xiuya Li, and Jie Huang contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13238-020-00713-x) contains supplementary material, which is available to authorized users.
© The Author(s) 2020
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.
KEYWORDS circadian gene BMAL1, human embryonic stem cells, cell differentiation, cardiomyocytes, dilated cardiomyopathy, mitochondria INTRODUCTION The circadian clock, also 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 rota
Data Loading...
