Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness
| Autor: | Alexander L. Hyde, Ugur Unluturk, David Jacobi, William B. Mair, Xiaohui Kong, Chih-Hao Lee, Nora Kory, Xiaobo Li, Sihao Liu, Nelson H. Knudsen, Kristopher Burkewitz, Matthew R. Gangl, Ryan K. Alexander |
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| Rok vydání: | 2015 |
| Předmět: |
FIS1
endocrine system Bioenergetics Physiology Longevity CLOCK Proteins Mitochondrion Biology medicine.disease_cause Diet High-Fat Mitochondrial Dynamics Article Mitochondrial Proteins Mice Cryptochrome Mitophagy medicine Animals Insulin Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology Cells Cultured Mice Knockout ARNTL Transcription Factors Cell Biology Cell biology Mitochondria CLOCK Cryptochromes Mice Inbred C57BL Oxidative Stress Liver Hepatocytes RNA Interference Oxidative stress Signal Transduction |
| Zdroj: | Cell Metabolism. 22(4):709-720 |
| ISSN: | 1550-4131 |
| DOI: | 10.1016/j.cmet.2015.08.006 |
| Popis: | SummaryMitochondria 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. |
| Databáze: | OpenAIRE |
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