Autonomous Redox Rhythms and Their Coupling to the Circadian Clock

Circadian rhythms have traditionally been considered to be outputs of genetic transcription-translation feedback loop (TTFL) oscillators. However, the discovery of circadian peroxiredoxin oxidation rhythms in anucleate red blood cells suggests that cells also possess an autonomous circadian redox rhythm. The conservation of this rhythm across all lineages of life, as well as in TTFL-defective backgrounds in multiple organisms, further indicates its importance. Rather than functioning as an isolated system, the redox rhythm is bidirectionally coupled to the genetic circadian clock. Perturbation of one oscillation may alter amplitude or shift period of the other, depending on biological context. In animals, the interplay between the redox rhythm and the genetic clock is complex, and the biological significance of the redox oscillation has yet to be established. In plants, immune-related redox perturbation by salicylic acid can reinforce the genetic clock, while the redox rhythm itself gates immune-induced programmed cell death toward morning as a circadian output. We propose that the redox rhythm reflects an intrinsic metabolic cycling in which cells alternate between the high-metabolic states that generate energy, reducing power, and reactive oxygen species (ROS), and the lower-metabolic states that favor detoxification, repair, and restoration of redox homeostasis. In this model, the redox rhythm is driven by the feedback between glycolysis, pentose phosphate pathway, ROS production via electron transport chains, antioxidant capacity, and cellular repair, and becomes entrained to the external cues via diurnal energy generation such as photosynthesis in green lineages.