Glycolysis under Circadian Control

Abstract

Glycolysis is considered a main metabolic pathway in highly proliferative cells, including endothelial, epithelial, immune, and cancer cells. Although oxidative phosphorylation (OXPHOS) is more efficient in ATP production per mole of glucose, proliferative cells rely predominantly on aerobic glycolysis, which generates ATP faster compared to OXPHOS and provides anabolic substrates to support cell proliferation and migration. Cellular metabolism, including glucose metabolism, is under strong circadian control. Circadian clocks control a wide array of metabolic processes, including glycolysis, which exhibits a distinct circadian pattern. In this review, we discuss circadian regulations during metabolic reprogramming and key steps of glycolysis in activated, highly proliferative cells. We suggest that the inhibition of metabolic reprogramming in the circadian manner can provide some advantages in the inhibition of oxidative glycolysis and a chronopharmacological approach is a promising way to treat diseases associated with up-regulated glycolysis.

Keywords: circadian; clock genes; glycolysis; metabolic reprogramming; oxidative phosphorylation.

Figure 1

Schematic diagram of the transcription-translation feedback loop (TTFL) at the molecular level. First, the regulatory loop is mediated by the proteins CLOCK and BMAL1 that heterodimerize and bind to E-box of several clock genes, including Per, Cry, Rev-erbα, and other genes. The proteins PER and CRY form a complex that inhibits CLOCK and BMAL1 transcription. The activity of the second regulatory loop can be modulated by REV-ERBα, which induces and represses Bmal1 gene expression, respectively. In the third regulatory loop, the activator DBP induces expression of D-box containing clock-controlled genes. The DBP activator is inhibited by NFIL3, whose transcription is regulated by REV-ERBα and RORs. Regulatory loops ensure the rhythmic expression of the core clock genes, which can regulate cellular metabolism, including glycolysis. In this scheme, blue boxes indicate circadian-regulated metabolic genes that exhibit a circadian pattern. Abbreviations: BMAL1—brain and muscle ARNT-like 1; CLOCK—circadian locomotor output; Cry—cryptochrome; DBP—D-box binding protein; D-CCGs—D-box containing clock controlled genes; fructose-1,6-P—fructose 1,6-bisphosphate; fructose-6-P—fructose-6-phosphate; fructose-2,6-BP—fructose-2,6-bisphosphate; glucose-6-P—glucose-6-phosphate GLUT—glucose transporter; NFIL3—nuclear factor interleukin-3 regulated protein; Per—period; REV-ERBα- nuclear receptor subfamily 1 group D member 1; RORE—ROR responsive element; PFKFB3—6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PFK-1—phosphofructokinase.

Figure 2

Crosstalk between HIF-1, circadian clocks, and glycolysis. (A) Under a normoxic condition, HIF-1α is ubiquitinated and degraded. In a hypoxia condition, HIF-1α translocates to the nucleus, binds to the HIF-1β and p300, and forms the HIF complex. This complex binds to hypoxia-response elements (HRE) and regulates the expression of glucose transporters and glycolytic enzymes. (B) HIF can interact with circadian pathways. CLOCK can interact with HIF-1β and p300 and binds to HRE. Additionally, HIF-1α can colocalize with BMAL1 to increase the expression of HIF- and clock-controlled genes. (C) Schematic representation of glycolytic metabolism regulated by the HIF-1α factor. Red boxes indicate gene expression regulated by HIF-1α. Pyruvate can be metabolized into lactate in a hypoxic condition (anaerobic glycolysis) or a condition of sufficient oxygen (aerobic glycolysis). In the process of OXPHOS, pyruvate is metabolized to Acetyl-CoA. Abbreviations: BMAL1—brain and muscle ARNT-like 1; CLOCK—circadian locomotor output; GLUT—glucose transporter; glyceraldehyde-3-P—glyceraldehyde-3-phosphate; HRE—hormone responsive element; HIF—hypoxia inducible factor; PFKFB3—6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PFK-1—phosphofructokinase; fructose-1,6-P—fructose 1,6-bisphosphate; fructose-6-P—fructose-6-phosphate; fructose-2,6-BP—fructose-2,6-bisphosphate; glucose-6-P—glucose-6-phosphate; OXPHOS—oxidative phosphorylation; PDH—pyruvate dehydrogenase; PDK1—pyruvate dehydrogenase kinase 1.