Cellular Timekeeping: It’s Redox o’Clock

Abstract

Mounting evidence in recent years supports the extensive interaction between the circadian and redox systems. The existence of such a relationship is not surprising because most organisms, be they diurnal or nocturnal, display daily oscillations in energy intake, locomotor activity, and exposure to exogenous and internally generated oxidants. The transcriptional clock controls the levels of many antioxidant proteins and redox-active cofactors, and, conversely, the cellular redox poise has been shown to feed back to the transcriptional oscillator via redox-sensitive transcription factors and enzymes. However, the circadian cycles in the -sulfinylation of the peroxiredoxin (PRDX) proteins constituted the first example of an autonomous circadian redox oscillation, which occurred independently of the transcriptional clock. Importantly, the high phylogenetic conservation of these rhythms suggests that they might predate the evolution of the transcriptional oscillator, and therefore could be a part of a primordial circadian redox/metabolic oscillator. This discovery forced the reappraisal of the dogmatic transcription-centered view of the clockwork and opened a new avenue of research. Indeed, the investigation into the links between the circadian and redox systems is still in its infancy, and many important questions remain to be addressed.

Quantitative Studies for Cell-Division Cycle Control

“…However, ample evidence underlines the important contributions of metabolic oscillations for circadian transcriptional control in physiological situations. The expression of circadian genes is mediated by metabolites, such as NAD, acetyl CoA, and ATP, via chromatin remodeling complexes (Imai, 2010; Koike et al, 2012; Reddy and Rey, 2014; Milev and Reddy, 2015; Mellor, 2016; Milev et al, 2018). These studies suggest that the transcriptional oscillator in mammalian cells and budding yeast is coupled with the metabolic oscillator via chromatin remodeling complexes (Figure 5D).…”

Time zones of pancreatic islet metabolism

“…Per1 and Per2 also serve as immediate early genes in the synchronization of the molecular clock circuitry, stimulated by multiple immediate early transcription factors: the cAMP responsive element (CRE) binding protein (CREB), the heat shock transcription factor 1 (HSF1) binding to heat shock elements (HSE), the serum response factor (SRF) binding to serum response elements (SRE) and the glucocorticoid receptor (GR) binding to glucocorticoid responsive elements (GRE). A redox oscillator (RO) of unknown molecular makeup drives circadian cycles of peroxiredoxin (PRX) oxidations 16,17 panel). αand β-cellular circadian oscillators accomplish complementary tasks in orchestrating αand β-cell gene transcription, by regulating the principal function of these cells, which is the secretion of the counter hormones glucagon and insulin.…”

Longevity strategies in response to light in the reef coral Stylophora pistillata

“…Additional evidence, notably a more extended list of clock genes, will be required to prove this hypothesis and determine whether it represents a widespread strategy among cnidarians. As recent studies continue to reveal connections between the transcriptional clock, autonomously oscillating redox and metabolic systems, or aging, endosymbiotic cnidarians may prove to be interesting models for deciphering these relationships 19,20 .…”

“…This hypothesis is supported by our KD experiments in human fibroblasts, which revealed a protective role in their orthologs. Mechanisms behind both anticipation and adjustment strategies may be relevant to the aging process since molecular damages accumulate faster during time shifts between raises in damaging sources and corresponding defense mechanisms 1,19,20 . The precise functions and mechanisms of action of these candidate genes or their paralogs remain poorly described, which suggests that they may harbor original functions that are key to the exceptional resistance and longevity exhibited by corals and that they may have unsuspected benefits in humans.…”

“…Some specific mechanisms of oxic stress resistance have been identified in corals 6 , 7 , 14 – 16 ; however, their contribution to the extreme longevity of these animals remains unknown. Obviously, as exposure to daylight is the main driver of symbiotic corals physiology, these resistance mechanisms are linked to circadian rhythms 6 , 17 – 19 , but, interestingly, even in mammals, circadian molecular clocks are crucial for stress management and their dysfunctions can result in aging phenotypes 20 . This suggest very ancient evolutionary links between these processes, echoing with the common origin of cryptochrome proteins from the core molecular clocks and light-induced UV damage-repairing photolyases 21 .…”