title: Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness.
abstract: Mitochondria undergo architectural/functional changes in response to metabolic inputs. How this process is regulated in physiological feeding/fasting states remains unclear. Here we show that mitochondrial dynamics (notably fission and mitophagy) and biogenesis are transcriptional targets of the circadian regulator Bmal1 in mouse liver and exhibit a metabolic rhythm in sync with diurnal bioenergetic demands. Bmal1 loss-of-function causes swollen mitochondria incapable of adapting to different nutrient conditions accompanied by diminished respiration and elevated oxidative stress. Consequently, liver-specific Bmal1 knockout (LBmal1KO) mice accumulate oxidative damage and develop hepatic insulin resistance. Restoration of hepatic Bmal1 activities in high-fat-fed mice improves metabolic outcomes, whereas expression of Fis1, a fission protein that promotes quality control, rescues morphological/metabolic defects of LBmal1KO mitochondria. Interestingly, Bmal1 homolog AHA-1 in C. elegans retains the ability to modulate oxidative metabolism and lifespan despite lacking circadian regulation. These results suggest clock genes are evolutionarily conserved energetics regulators.
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jacobi
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Sihao
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Burkewitz
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Kory
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Nelson H
authors.initials: NH
authors.lastname: Knudsen
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Alexander
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Ugur
authors.initials: U
authors.lastname: Unluturk
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Hyde
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Gangl
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Mair
authors.affiliation: Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: clee@hsph.harvard.edu.
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Lee
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008136:Longevity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D029742:Caenorhabditis elegans Proteins; C538964:Cry1 protein, mouse; D056931:Cryptochromes; C561064:FIS1 protein, mouse; D007328:Insulin; D024101:Mitochondrial Proteins; D056926:CLOCK Proteins; C538944:Clock protein, mouse