Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness

Abstract

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 homologue 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.

Immunometabolism: Is it under the eye of the clock?

“…• Increased mitochondrial ROS [93] • Decreased NAD+ and ATP. Decreased triglycerides [95] Pancreas • Diabetes due to loss of glucose induced insulin secretion [76] • Increased ROS [76] Myeloid…”

“…Mitochondria themselves are dynamically changing via fission, fusion and mitophagy, collectively termed "mitochondrial dynamics", allowing them to respond to changes in metabolic inputs and energy demands [92]. Hepatic BMAL1 has been linked to the control of mitochondrial dynamics and production of mitochondrial ROS from mitochondrial oxidative phosphorylation [93]. In liver specific Bmal1-/-mice, a circadian rhythm in mitochondrial dynamics was discovered [93].…”

“…Hepatic BMAL1 has been linked to the control of mitochondrial dynamics and production of mitochondrial ROS from mitochondrial oxidative phosphorylation [93]. In liver specific Bmal1-/-mice, a circadian rhythm in mitochondrial dynamics was discovered [93]. Many of the genes involved in mitochondrial dynamics such as mitochondrial fission protein1 (Fis1), BCL2/adenovirus E1B 19 kdinteracting protein 3 (Bnip3), and PTEN-induced putative kinase 1 (Pink1) display a diurnal rhythm in WT mice that was ablated in the liver specific Bmal1-/-mice [93].…”

“…In liver specific Bmal1-/-mice, a circadian rhythm in mitochondrial dynamics was discovered [93]. Many of the genes involved in mitochondrial dynamics such as mitochondrial fission protein1 (Fis1), BCL2/adenovirus E1B 19 kdinteracting protein 3 (Bnip3), and PTEN-induced putative kinase 1 (Pink1) display a diurnal rhythm in WT mice that was ablated in the liver specific Bmal1-/-mice [93]. In WT mice increased fusion was observed during the resting period, followed by subsequent fission and mitophagy during the active phase.…”

“…For example mitochondria have been linked to regulation of NOD-Like-Receptor family member X1 (NLRX1), TNF receptor associated factor (TRAF6) and NOD-Like-Receptor protein 3 (NLRP3) [94]. Similarly to the role of BMAL1 described in the liver [93], BMAL1 in macrophages may affect mitochondrial health and bioenergetics which may in turn lead to alterations in pathogen sensing and host response.…”