Role and Possible Mechanism of Clock Gene Rev-erbα in Exercise-induced Mitochondrial Biogenesis / 生物化学与生物物理进展

ABSTRACT

The clock gene Rev-erbα, also known as nuclear receptor subfamily 1 group D member 1 (Nr1d1), is a crucial regulatory factor in organisms. It exhibits circadian rhythmic expression in metabolically active tissues such as skeletal muscles, heart, liver, and adipose tissue, responding to various environmental stimuli. Rev-erbα plays a significant role in regulating circadian rhythms, metabolic homeostasis, and other physiological processes, earning its designation as an “integrator” of the circadian system and metabolism. Rev-erbα establishes complex connections with other clock genes through the transcriptional-translational feedback loop (TTFL), which is important for the rhythmic output of biological clock system and for the relative stability of phases and cycles. Mitochondrial biogenesis is a physiological process initiated by cells to maintain energy homeostasis by using existing mitochondria as a template for self-growth and division. As the “energy factory” of organism, disruptions in mitochondrial biogenesis are closely associated with the development of various diseases. Studies have shown that not only the factors involved in mitochondrial biogenesis have circadian oscillations, but also the morphology, dynamics and energy metabolism of mitochondria themselves have cyclic fluctuations throughout the day, suggesting that mitochondrial biogenesis is regulated by the biological clock system, in which the clock gene Rev-erbα plays a key role, it drives mitochondrial biogenesis and synergistically regulates autophagy to normalize a number of physiological processes in the body. Rev-erbα is sensitive to both internal and external environmental changes, and disruptions in circadian rhythms, metabolic diseases, and aging are significant inducers of changes in Rev-erbα expression, and its concomitant inflammation and oxidative stress may be an intrinsic mechanism for inhibiting mitochondrial biogenesis. Therefore, the enhancement of mitochondrial biogenesis by regulating the Rev-erbα activity status may be an important way to improve the pathology and promote the health of organism. Exercise, as a commonly accepted non-pharmacological tool, plays an important role in enhancing mitochondrial biogenesis and promoting health. It has been found that there is a close relationship between exercise and Rev-erbα. On the one hand, exercise stimulation directly affects the expression of Rev-erbα, especially high-intensity and long-term regular exercise; on the other hand, Rev-erbα achieves indirect regulation of exercise capacity by mediating processes such as skeletal muscle mitochondrial biogenesis and autophagy, muscle mass maintenance, energy metabolism and skeletal muscle regeneration. Based on the above findings, it is hypothesized that Rev-erbα may serve as a key bridge between exercise and mitochondrial biogenesis. Exercise enhances the transcriptional response of Rev-erbα in the nucleus, upregulates the expression of Rev-erbα protein in cytoplasm, activates the AMP-activated proteinkinase (AMPK)/ silent information regulator 1 (SIRT1)/peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, regulates Ca2+ flux and downstream signaling molecules; meanwhile, exercise can upregulate antioxidant gene expression and alleviate oxidative stress through Rev-erbα, which ultimately enhances the function of mitochondria, and promotes mitochondrial biogenesis. In conclusion, the clock gene Rev-erbα emerges as a crucial target for exercise-induced enhancement of mitochondrial biogenesis. In this paper, the biological characteristics ofRev-erbα, the role of Rev-erbα in regulating mitochondrial biogenesis and the factors that may influence it, the interaction between exercise and Rev-erbα, and the potential mechanism of exercise-induced mitochondrial biogenesis via Rev-erbα are sorted out and discussed, which can provide theoretical references to the mechanism of exercise-promoted mitochondrial biogenesis.