A Robust Model for Circadian Redox Oscillations

Abstract

The circadian clock is an endogenous oscillator that controls daily rhythms in metabolism, physiology and behavior. Although the timekeeping components differ among species, a common design principle is a transcription-translation negative feedback loop. However, it is becoming clear that other mechanisms can contribute to the generation of 24 h rhythms. In mammalian adrenal gland, heart and brown adipose tissue, peroxiredoxins (Prx) exhibit 24 h rhythms in their redox state. Such rhythms are generated as a result of an inactivating hyperoxidation reaction that is reduced by coordinated import of the sulfiredoxin (Srx) into the mitochondria. However, a quantitative description of the Prx/Srx oscillating system is still missing. We investigate the basic principles that generate mitochondrial Prx/Srx rhythms using computational modeling. We observe that the previously described delay in mitochondrial Srx import, in combination with an appropriate separation of fast and slow reactions is sufficient to generate robust self-sustained relaxation-like oscillations. We find that our conceptual model can be regarded as a series of three consecutive phases and two temporal switches, highlighting the importance of delayed negative feedback and switches in the generation of oscillations.