A Robust Model for Circadian Redox Oscillations.

Marta Del Olmo,Achim Kramer,Hanspeter Herzel

doi:10.3390/ijms20092368

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. Peroxiredoxins (Prxs) exhibit 24 h rhythms in their redox state in all kingdoms of life. In mammalian adrenal gland, heart and brown adipose tissue, such rhythms are generated as a result of an inactivating hyperoxidation reaction that is reduced by coordinated import of 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.

Highlights

The Earth’s regular 24 h rotation has led to the evolution of circadian oscillators in all kingdoms of life
Prx3 is one of the major antioxidant proteins involved in H2O2 removal in mitochondria
We have designed the first model for the complex biochemical system of Prx3-SO2H/Srx redox oscillations and we find that the loop Prx3-SOH – Prx3-SO2H, together with the negative feedback mediated by Srx (Figure 1B), is necessary and sufficient for the generation of oscillations

Summary

Introduction

The Earth’s regular 24 h rotation has led to the evolution of circadian oscillators in all kingdoms of life. The molecular clockwork components have widely divergent origins and are not conserved across the main divisions of life, a common design principle has been applied to all organisms where circadian timing mechanisms have been investigated. This paradigm relies on a negative transcription-translation feedback loop (TTFL), where protein products of clock genes feed back periodically to regulate their own expression and drive rhythmic output pathways and physiology [2,4,5]. Some examples of non-transcriptional oscillators are (i) the cyanobacterial phosphorylation oscillator, which can be reconstituted in vitro [6]; (ii) the circadian photosynthetic rhythms that persist in green algae after enucleation and in the absence of nuclear transcription [7]; or (iii) the peroxiredoxin oxidation rhythms found in red blood cells [8], which are anucleate

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