FIG. 3.

Circadian interaction with transcriptional regulation of antioxidant defense system. Core clock components drive the rhythmic expression of Nrf2. Mitochondrial H₂O₂ that escapes the mitochondria rhythmically inhibits KEAP1, which allows NRF2 to translocate into the nucleus and regulate expression of mitochondrial antioxidant defense enzymes and pentose phosphate pathway enzymes. NRF2 interacts with the core clock through positive feedback to regulate its own expression. Mitochondrial H₂O₂ drives PPAR nuclear receptors to inhibit activity of NF-κB and is speculated to promote activity of core clock transcriptional regulation for management of mitochondrial oxidative stress enzymes. KEAP1, Kelch-like ECH-associated protein 1; NF-κB, nuclear factor-κB; NRF2, nuclear factor erythroid-2-related factor 2; PPAR, peroxisome proliferator-activated receptor.