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

doi:10.1007/s13238-020-00713-x

Protein Cell

2020, Vol. 11

Issue (9) : 661-679 https://doi.org/10.1007/s13238-020-00713-x

RESEARCH ARTICLE

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

Ermin Li¹, Xiuya Li¹, Jie Huang¹, Chen Xu¹, Qianqian Liang¹, Kehan Ren², Aobing Bai¹, Chao Lu^1,^4,⁵(

), Ruizhe Qian^1,^4,⁵(

), Ning Sun^1,^3,^4,⁵(

)

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

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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.

Keywords circadian gene BMAL1 human embryonic stem cells cell differentiation cardiomyocytes dilated cardiomyopathy mitochondria

Corresponding Author(s): Chao Lu,Ruizhe Qian,Ning Sun

Online First Date: 14 September 2020 Issue Date: 25 September 2020

Cite this article:

Ermin Li,Xiuya Li,Jie Huang, et al. BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy[J]. Protein Cell, 2020, 11(9): 661-679.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-020-00713-x
https://academic.hep.com.cn/pac/EN/Y2020/V11/I9/661

1	FJ Alibhai, J LaMarre, CJ Reitz, EV Tsimakouridze, JT Kroetsch, SS Bolz, A Shulman, S Steinberg, TP Burris, GY Ouditet al. (2017) Disrupting the key circadian regulator CLOCK leads to age-dependent cardiovascular disease. J Mol Cell Cardiol 105:24–37 https://doi.org/10.1016/j.yjmcc.2017.01.008
2	FJ Alibhai, CJ Reitz, WT Peppler, P Basu, P Sheppard, E Choleris, M Bakovic, TA Martino (2018) Female ClockDelta19/Delta19 mice are protected from the development of age-dependent cardiomyopathy. Cardiovasc Res 114:259–271 https://doi.org/10.1093/cvr/cvx185
3	YS Ang, RN Rivas, AJS Ribeiro, R Srivas, J Rivera, NR Stone, K Pratt, TMA Mohamed, JD Fu, CI Spenceret al. (2016) Disease model of GATA4 mutation reveals transcription factor cooperativity in human cardiogenesis. Cell 167(1734–1749):e1722 https://doi.org/10.1016/j.cell.2016.11.033
4	MB Azad, Y Chen, ES Henson, J Cizeau, E McMillan-Ward, SJ Israels, SB Gibson (2008) Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy 4:195–204 https://doi.org/10.4161/auto.5278
5	A Balsalobre, F Damiola, U Schibler (1998) A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93:929–937 https://doi.org/10.1016/S0092-8674(00)81199-X
6	DM Bers (2002) Cardiac excitation-contraction coupling. Nature 415:198–205 https://doi.org/10.1038/415198a
7	JM Bravo-San Pedro, G Kroemer, L Galluzzi (2017) Autophagy and mitophagy in cardiovascular disease. Circ Res 120:1812–1824 https://doi.org/10.1161/CIRCRESAHA.117.311082
8	MS Bray, ME Young (2008) Diurnal variations in myocardial metabolism. Cardiovasc Res 79:228–237 https://doi.org/10.1093/cvr/cvn054
9	MS Bray, CA Shaw, MW Moore, RA Garcia, MM Zanquetta, DJ Durgan, WJ Jeong, JY Tsai, H Bugger, D Zhanget al. (2008) Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression. Am J Physiol Heart Circ Physiol 294:H1036–1047 https://doi.org/10.1152/ajpheart.01291.2007
10	MK Bunger, LD Wilsbacher, SM Moran, C Clendenin, LA Radcliffe, JB Hogenesch, MC Simon, JS Takahashi, CA Bradfield (2000) Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103:1009–1017 https://doi.org/10.1016/S0092-8674(00)00205-1
11	AH Chaanine, RE Gordon, E Kohlbrenner, L Benard, D Jeong, RJ Hajjar (2013) Potential role of BNIP3 in cardiac remodeling, myocardial stiffness, and endoplasmic reticulum: mitochondrial calcium homeostasis in diastolic and systolic heart failure. Circ Heart Fail 6:572–583 https://doi.org/10.1161/CIRCHEARTFAILURE.112.000200
12	H Cheng, WJ Lederer, MB Cannell (1993) Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science 262:740–744 https://doi.org/10.1126/science.8235594
13	W Deng, S Zhu, L Zeng, J Liu, R Kang, M Yang, L Cao, H Wang, TR Billiar, J Jianget al. (2018) The circadian clock controls immune checkpoint pathway in sepsis. Cell Rep 24:366–378 https://doi.org/10.1016/j.celrep.2018.06.026
14	P Dierickx, LW Van Laake, N Geijsen (2018) Circadian clocks: from stem cells to tissue homeostasis and regeneration. EMBO Rep 19:18–28 https://doi.org/10.15252/embr.201745130
15	DA Eisner, JL Caldwell, K Kistamas, AW Trafford (2017) Calcium and excitation-contraction coupling in the heart. Circ Res 121:181–195 https://doi.org/10.1161/CIRCRESAHA.117.310230
16	D Fatkin, C MacRae, T Sasaki, MR Wolff, M Porcu, M Frenneaux, J Atherton, HJ Jr Vidaillet, S Spudich, U De Girolamiet al. (1999) Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 341:1715–1724 https://doi.org/10.1056/NEJM199912023412302
17	EE Flynn-Evans, JA Shekleton, B Miller, LJ Epstein, D Kirsch, LA Brogna, LM Burke, E Bremer, JM Murray, P Gehrmanet al. (2017) Circadian phase and phase angle disorders in primary insomnia. Sleep. https://doi.org/10.1093/sleep/zsx163
18	MW Friederich, S Timal, CA Powell, C Dallabona, A Kurolap, S Palacios-Zambrano, D Bratkovic, TGJ Derks, D Bick, K Boumanet al. (2018) Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder. Nat Commun 9:4065 https://doi.org/10.1038/s41467-018-06250-w
19	B Gerull, M Gramlich, J Atherton, M McNabb, K Trombitas, S Sasse-Klaassen, JG Seidman, C Seidman, H Granzier, S Labeitet al. (2002) Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 30:201–204 https://doi.org/10.1038/ng815
20	AM Gomez, HH Valdivia, H Cheng, MR Lederer, LF Santana, MB Cannell, SA McCune, RA Altschuld, WJ Lederer (1997) Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 276:800–806 https://doi.org/10.1126/science.276.5313.800
21	F Hatanaka, C Matsubara, J Myung, T Yoritaka, N Kamimura, S Tsutsumi, A Kanai, Y Suzuki, P Sassone-Corsi, H Aburataniet al. (2010) Genome-wide profiling of the core clock protein BMAL1 targets reveals a strict relationship with metabolism. Mol Cell Biol 30:5636–5648 https://doi.org/10.1128/MCB.00781-10
22	DB Hoover, CE Ganote, SM Ferguson, RD Blakely, RL Parsons (2004) Localization of cholinergic innervation in guinea pig heart by immunohistochemistry for high-affinity choline transporters. Cardiovasc Res 62:112–121 https://doi.org/10.1016/j.cardiores.2004.01.012
23	N Huang, Y Chelliah, Y Shan, CA Taylor, SH Yoo, C Partch, CB Green, H Zhang, JS Takahashi (2012) Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex. Science 337:189–194 https://doi.org/10.1126/science.1222804
24	H Iwashita, S Torii, N Nagahora, M Ishiyama, K Shioji, K Sasamoto, S Shimizu, K Okuma (2017) Live cell imaging of mitochondrial autophagy with a novel fluorescent small molecule. ACS Chem Biol 12:2546–2551 https://doi.org/10.1021/acschembio.7b00647
25	D Jacobi, S Liu, K Burkewitz, N Kory, NH Knudsen, RK Alexander, U Unluturk, X Li, X Kong, AL Hydeet al. (2015) Hepatic Bmal1 regulates rhythmic mitochondrial dynamics and promotes metabolic fitness. Cell Metab 22:709–720 https://doi.org/10.1016/j.cmet.2015.08.006
26	M Kanevskij, G Taimor, M Schafer, HM Piper, KD Schluter (2002) Neuropeptide Y modifies the hypertrophic response of adult ventricular cardiomyocytes to norepinephrine. Cardiovasc Res 53:879–887 https://doi.org/10.1016/S0008-6363(01)00517-X
27	TH Kang, JT Reardon, M Kemp, A Sancar (2009) Circadian oscillation of nucleotide excision repair in mammalian brain. Proc Natl Acad Sci U S A 106:2864–2867 https://doi.org/10.1073/pnas.0812638106
28	RE Kreipke, SJ Birren (2015) Innervating sympathetic neurons regulate heart size and the timing of cardiomyocyte cell cycle withdrawal. J Physiol 593:5057–5073 https://doi.org/10.1113/JP270917
29	F Lan, RE Collins, R De Cegli, R Alpatov, JR Horton, X Shi, O Gozani, X Cheng, Y Shi (2007) Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-mediated gene repression. Nature 448:718–722 https://doi.org/10.1038/nature06034
30	H Lee, Y Yoon (2016) Mitochondrial fission and fusion. Biochem Soc Trans 44:1725–1735 https://doi.org/10.1042/BST20160129
31	M Lefta, KS Campbell, HZ Feng, JP Jin, KA Esser (2012) Development of dilated cardiomyopathy in Bmal1-deficient mice. Am J Physiol Heart Circ Physiol 303:H475–485 https://doi.org/10.1152/ajpheart.00238.2012
32	L Li, J Desantiago, G Chu, EG Kranias, DM Bers (2000) Phosphorylation of phospholamban and troponin I in beta-adrenergicinduced acceleration of cardiac relaxation. Am J Physiol Heart Circ Physiol 278:H769–779 https://doi.org/10.1152/ajpheart.2000.278.3.H769
33	X Lian, C Hsiao, G Wilson, K Zhu, LB Hazeltine, SM Azarin, KK Raval, J Zhang, TJ Kamp, SP Palecek (2012) Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci U S A 109:E1848–1857 https://doi.org/10.1073/pnas.1200250109
34	K Maemura, MD Layne, M Watanabe, MA Perrell, R Nagai, ME Lee (2001) Molecular mechanisms of morning onset of myocardial infarction. Ann N Y Acad Sci 947:398–402 https://doi.org/10.1111/j.1749-6632.2001.tb03972.x
35	BJ Maron, JA Towbin, G Thiene, C Antzelevitch, D Corrado, D Arnett, AJ Moss, CE Seidman, JB Young, American Heart Associationet al. (2006) Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 113:1807–1816 https://doi.org/10.1161/CIRCULATIONAHA.106.174287
36	E Maury, HK Hong, J Bass (2014) Circadian disruption in the pathogenesis of metabolic syndrome. Diabetes Metab 40:338–346 https://doi.org/10.1016/j.diabet.2013.12.005
37	MJ McManus, M Picard, HW Chen, HJ De Haas, P Potluri, J Leipzig, A Towheed, A Angelin, P Sengupta, RM Morrowet al. (2019) Mitochondrial DNA variation dictates expressivity and progression of nuclear DNA mutations causing cardiomyopathy. Cell Metab 29(78–90):e75 https://doi.org/10.1016/j.cmet.2018.08.002
38	P McNamara, SB Seo, RD Rudic, A Sehgal, D Chakravarti, GA FitzGerald (2001) Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell 105:877–889 https://doi.org/10.1016/S0092-8674(01)00401-9
39	CJ Morris, TE Purvis, K Hu, FA Scheer (2016) Circadian misalignment increases cardiovascular disease risk factors in humans. Proc Natl Acad Sci U S A 113:E1402–1411 https://doi.org/10.1073/pnas.1516953113
40	S Mottillo, KB Filion, J Genest, L Joseph, L Pilote, P Poirier, S Rinfret, EL Schiffrin, MJ Eisenberg (2010) The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 56:1113–1132 https://doi.org/10.1016/j.jacc.2010.05.034
41	E Murphy, H Ardehali, RS Balaban, F DiLisa, GW 2nd Dorn, RN Kitsis, K Otsu, P Ping, R Rizzuto, MN Sacket al. (2016) Mitochondrial function, biology, and role in disease: a scientific statement from the American Heart Association. Circ Res 118:1960–1991 https://doi.org/10.1161/RES.0000000000000104
42	D Narendra, LA Kane, DN Hauser, IM Fearnley, RJ Youle (2010) p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 6:1090–1106 https://doi.org/10.4161/auto.6.8.13426
43	H Nonaka, N Emoto, K Ikeda, H Fukuya, MS Rohman, SB Raharjo, K Yagita, H Okamura, M Yokoyama (2001) Angiotensin II induces circadian gene expression of clock genes in cultured vascular smooth muscle cells. Circulation 104:1746–1748 https://doi.org/10.1161/hc4001.098048
44	TD O’Connell , S Ishizaka, A Nakamura, PM Swigart, MC Rodrigo, GL Simpson, S Cotecchia, DG Rokosh, W Grossman, E Fosteret al. (2003) The alpha(1A/C)- and alpha(1B)-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse. J Clin Invest 111:1783–1791 https://doi.org/10.1172/JCI200316100
45	SB Parks, JD Kushner, D Nauman, D Burgess, S Ludwigsen, A Peterson, D Li, P Jakobs, M Litt, CB Porteret al. (2008) Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am Heart J 156:161–169 https://doi.org/10.1016/j.ahj.2008.01.026
46	CL Partch, CB Green, JS Takahashi (2014) Molecular architecture of the mammalian circadian clock. Trends Cell Biol 24:90–99 https://doi.org/10.1016/j.tcb.2013.07.002
47	CB Peek, AH Affinati, KM Ramsey, HY Kuo, W Yu, LA Sena, O Ilkayeva, B Marcheva, Y Kobayashi, C Omuraet al. (2013) Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science 342:1243417 https://doi.org/10.1126/science.1243417
48	V 3rd Piacentino, CR Weber, X Chen, J Weisser-Thomas, KB Margulies, DM Bers, SR Houser (2003) Cellular basis of abnormal calcium transients of failing human ventricular myocytes. Circ Res 92:651–658 https://doi.org/10.1161/01.RES.0000062469.83985.9B
49	JH Pyun, HJ Kim, MH Jeong, BY Ahn, TA Vuong, DI Lee, S Choi, SH Koo, H Cho, JS Kang (2018) Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation. Nat Commun 9:5107 https://doi.org/10.1038/s41467-018-07606-y
50	G Rey, UK Valekunja, KA Feeney, L Wulund, NB Milev, A Stangherlin, L Ansel-Bollepalli, V Velagapudi, JS O’Neill, AB Reddy (2016) The Pentose Phosphate Pathway Regulates the Circadian Clock. Cell Metab 24:462–473 https://doi.org/10.1016/j.cmet.2016.07.024
51	JP Schmitt, M Kamisago, M Asahi, GH Li, F Ahmad, U Mende, EG Kranias, DH MacLennan, JG Seidman, CE Seidman (2003) Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 299:1410–1413 https://doi.org/10.1126/science.1081578
52	K Schmitt, A Grimm, R Dallmann, B Oettinghaus, LM Restelli, M Witzig, N Ishihara, K Mihara, JA Ripperger, U Albrechtet al. (2018) Circadian control of DRP1 activity regulates mitochondrial dynamics and bioenergetics. Cell Metab 27(657–666): e655 https://doi.org/10.1016/j.cmet.2018.01.011
53	J Shan, A Kushnir, MJ Betzenhauser, S Reiken, J Li, SE Lehnart, N Lindegger, M Mongillo, PJ Mohler, AR Marks (2010) Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice. J Clin Invest 120:4388–4398 https://doi.org/10.1172/JCI32726
54	M Song, K Mihara, Y Chen, L Scorrano, GW 2nd Dorn (2015) Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab 21:273–286 https://doi.org/10.1016/j.cmet.2014.12.011
55	M Song, A Franco, JA Fleischer, L Zhang, GW 2nd Dorn (2017) Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence. Cell Metab 26(872–883):e875 https://doi.org/10.1016/j.cmet.2017.09.023
56	RG Stevens (2009) Light-at-night, circadian disruption and breast cancer: assessment of existing evidence. Int J Epidemiol 38:963–970 https://doi.org/10.1093/ije/dyp178
57	JS Takahashi (2017) Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet 18:164–179 https://doi.org/10.1038/nrg.2016.150
58	N Takeda, K Maemura (2010) Circadian clock and vascular disease. Hypertens Res 33:645–651 https://doi.org/10.1038/hr.2010.68
59	MF Tevy, J Giebultowicz, Z Pincus, G Mazzoccoli, M Vinciguerra (2013) Aging signaling pathways and circadian clock-dependent metabolic derangements. Trends Endocrinol Metab 24:229–237 https://doi.org/10.1016/j.tem.2012.12.002
60	HR Ueda, S Hayashi, W Chen, M Sano, M Machida, Y Shigeyoshi, M Iino, S Hashimoto (2005) System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet 37:187–192 https://doi.org/10.1038/ng1504
61	RB Vega, DP Kelly (2017) Cardiac nuclear receptors: architects of mitochondrial structure and function. J Clin Invest 127:1155–1164 https://doi.org/10.1172/JCI88888
62	PG Vikhorev, N Smoktunowicz, AB Munster, O Copeland, S Kostin, C Montgiraud, AE Messer, MR Toliat, A Li, CG Dos Remedioset al. (2017) Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes. Sci Rep 7:14829 https://doi.org/10.1038/s41598-017-13675-8
63	DC Wallace (2013) A mitochondrial bioenergetic etiology of disease. J Clin Invest 123:1405–1412 https://doi.org/10.1172/JCI61398
64	C Xiao, K Wang, Y Xu, H Hu, N Zhang, Y Wang, Z Zhong, J Zhao, Q Li, D Zhuet al. (2018) Transplanted mesenchymal stem cellsreduce autophagic flux in infarcted hearts via the exosomal transfer of miR-125b. Circ Res 123:564–578 https://doi.org/10.1161/CIRCRESAHA.118.312758
65	M Yano, K Ono, T Ohkusa, M Suetsugu, M Kohno, T Hisaoka, S Kobayashi, Y Hisamatsu, T Yamamoto, M Kohnoet al. (2000) Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca(2+) leak through ryanodine receptor in heart failure. Circulation 102:2131–2136 https://doi.org/10.1161/01.CIR.102.17.2131
66	ME Young, P Razeghi, AM Cedars, PH Guthrie, H Taegtmeyer (2001) Intrinsic diurnal variations in cardiac metabolism and contractile function. Circ Res 89:1199–1208 https://doi.org/10.1161/hh2401.100741
67	ME Young, RA Brewer, RA Peliciari-Garcia, HE Collins, L He, TL Birky, BW Peden, EG Thompson, BJ Ammons, MS Brayet al. (2014) Cardiomyocyte-specific BMAL1 plays critical roles in metabolism, signaling, and maintenance of contractile function of the heart. J Biol Rhythms 29:257–276 https://doi.org/10.1177/0748730414543141

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