FIGURE 2.

Interactions between the circadian clock and peroxiredoxin cycle. The transcription factors CLOCK, NPAS2, and BMAL1 make up the positive arm of the transcriptional-translational feedback loop (TTFL) and control the expression of period (PER) and cryptochrome (CRY). PER and CRY make up the negative arm of the TTFL and inhibit the activity of CLOCK/BMAL1, forming a negative feedback loop. CLOCK(NPAS2)/BMAL1 controls the expression of various output genes (including Nrf2, Nqo1, and Aldh2), which influences ROS accumulation in the peroxiredoxin cycle. Sirtuin 1 (SIRT1), an NAD+-dependent histone and protein deacetylase, regulates the activity of the CLOCK/BMAL1 complex. Interestingly, melatonin (MT) acts as an antioxidant to inhibit ROS. Melatonin enters the mitochondria through MT transporters and is also synthesized within the mitochondria. Melatonin can also bind to MT receptors on the mitochondria to inhibit cytochrome c release, which may be protective against cell death