期刊
CELL METABOLISM
卷 22, 期 4, 页码 709-720出版社
CELL PRESS
DOI: 10.1016/j.cmet.2015.08.006
关键词
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资金
- National Institutes of Health Interdisciplinary Training in Genes and Environment grant [T32ES016645]
- Herchel Smith Graduate Fellowship
- American Heart Association
- NIH [F32AG044944, R01DK075046]
- Ellison Medical Foundation
- NIG [R01AG044346]
- American Diabetes Association [1-14-BS-122]
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.
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