[PDF][PDF] Hepatic Bmal1 regulates rhythmic mitochondrial dynamics and promotes metabolic fitness

D Jacobi, S Liu, K Burkewitz, N Kory, NH Knudsen… - Cell metabolism, 2015 - cell.com
D Jacobi, S Liu, K Burkewitz, N Kory, NH Knudsen, RK Alexander, U Unluturk, X Li, X Kong…
Cell metabolism, 2015cell.com
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 …
Summary
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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