At stress occurrence, changes in the redox state compromise cellular homeostasis, leading to a state of disequilibrium, with almost unknown consequences on the clock B. During a phase of recovery or strain, plants try to cope with the stress but how the clock behaves during this time is still uncertain C. A successful recovery will lead to a new dynamic equilibrium acclimation after stress exposure D.
When acclimated, plants maintain a state of memory for which they will possibly experience fewer disturbances from the next stress event E. In both acclimation and memory state the clock will maintain its functions but very little is known on its possible phase shifts D,E. On the contrary, if the stress becomes exceptionally destructive, the clock will succumb, plants will not recover and die F. Working clocks are coupled with identified physiological states of equilibrium while clock with the question marks represent the states where clock behavior is completely unknown.
The red cross signifies the complete disruption of the clock when plants die. The yellow lightening bolt represents stress occurrence. There are potentially beneficial aspects to stress, for instance stimulating improved resistance to future stress Larcher, Possibly, RNA turnover contributes to acclimation and stress memory, but there is no clear understanding of how this mechanism competes with the epigenetics in memory development Crisp et al. While clock function is retained, phase shifts are commonly associated with proximal stress response Figures 1D,E. However, changes in clock gene frequencies can be also part of an adaptive evolutionary response, as in crop plants undergoing selection for agronomically desirable traits Kevers et al.
While in rodents the connection between the circadian clock and stress response is well characterized Koch et al. Several stochastic models have successfully predicted clock activity at the molecular level in response to predictable variation in environmental cues Ruoff et al. However, circadian clocks also experience extrinsic noise, namely irregular fluctuations in the environment, which are mostly omitted from current process models Pokhilko et al. Yet, synchronized metabolic responses driven by the core oscillator seem to be fundamental in plant response to environmental stress Sanchez et al.
Based on studies in mammals and algae, it seems probable that acute oxidative stress can reset the clock, resulting in the concurrent activation of a network of circadian genes that will propagate an antioxidant, cell survival response Tamaru et al. This hypothesis considers H 2 O 2 as a signal transducer, relaying information about the external environment to the circadian pacemaker. Susceptibility to oxidative stress through disruption of the circadian oscillator is another proposed mechanism linking ROS and the expression of the circadian clock Qian et al.
Recovery is not merely a return to the pre-stress state, but is instead a regulated mechanism, and its resolution would help in predicting plant adjustments to changing environmental conditions. Moreover, it remains unclear how the clock behaves in extremely stressed plants close to mortality Sanchez et al. In this scenario, a functional characterization of the effects of environmental noise on the core oscillator is key to integrating metabolic information, such as ROS dynamics, into current clock models Einset et al. Chlorophyll a fluorescence is a fast, non-invasive method commonly used to assess plant performance Baker, ; Croce and van Amerongen, Although excessive ROS accumulation has been shown to occur together with changes in fluorescence parameters Aldea et al.
So far, no predictive understanding of the correlation between ROS and the fluorescence signal is possible and the association will depend on the stress type, intensity and duration. Dynamics of chlorophyll a fluorescence and derived parameters in response to abiotic stress in optimal light conditions. On the x-axis, the stress level is reported as a continuum between a minimum value at physiological equilibrium green shadow , passing through early sensing purple shadow and possible recovery yellow shadow , till death red shadow.
The y-axis represents fluorescence in arbitrary units: On the top part of the panel, working clocks are reported for the most studied physiological states while clock with the question marks represent the states where clock behavior is completely unknown.
Circadian Rhythms and Redox State in Plants: Till Stress Do Us Part
We emphasize the diurnal timing of plant response to abiotic stress can be critical, as we recently showed in Brassica rapa under mild drought stress Des Mairas, ; Greenham et al. During the day, a phase shift in expression pattern for genes related to photosystem efficiency and light response pathways e. Later, the same fluorescence parameters were observed to have rhythmicity in Arabidopsis mutants and barley under constant blue and white light conditions Litthauer et al.
Although it seems clear that redox state and the circadian clock are interlocked in stress response, it remains unknown if the clock is reset by stress and if any type of protective acclimation is triggered at the cell level. In this perspective, we propose that a timely avenue of research lies in investigating the details of the recovery phase from the stress. We suggest a more intensive use of chlorophyll a fluorescence to assess variation in circadian rhythms, and summarized the importance of fluorescence dynamics at different stress levels.
Fluorescence data as a high-throughput screen, coupled with ROS analysis, proteomic, metabolomics and gene expression, will inform and improve existing process models: CRG conceptualized, reviewed, validated formerly collected the data, and wrote the original draft of the manuscript.
BEE and CW acquired the funding and reviewed and edited the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We also thank Heather N. Dave Millar for critically reading the manuscript. National Center for Biotechnology Information , U. Journal List Front Plant Sci v. Published online Mar 5.
Ewers , 1, 2 and Cynthia Weinig 1, 2, 3. Received Dec 5; Accepted Feb The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Abstract A growing body of evidence demonstrates a significant relationship between cellular redox state and circadian rhythms.
Introduction The link between the circadian clock and oxygenic metabolism is likely to have originated with the rise in oxygen concentration 3 billion years ago, when early photosynthetic bacteria started to use water as an electron donor. Plant Circadian Rhythms All living things on Earth encounter daily oscillations in environmental factors. Ros Homeostasis Redox state indicates the balance of oxidized versus reduced forms of electron donors and acceptors in a cell. Clock and Redox State: Open in a separate window.
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Author Contributions CRG conceptualized, reviewed, validated formerly collected the data, and wrote the original draft of the manuscript. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The use of metabolomic quantitative trait locus mapping and osmotic adjustment traits for the improvement of crop yields under environmental stresses. Reactive oxygen species, antioxidants and signaling in plants. Plant molecular stress responses face climate change. A method for quantitative analysis of spatially variable physiological processes across leaf surfaces. The roles of reactive oxygen species in plant cells. Applications of chlorophyll fluorescence can improve crop production strategies: All in good time: ROS as key players in plant stress signalling.
Reactive oxygen species and peroxisomes: Evolutionary relationships among barley and Arabidopsis core circadian clock and clock-associated genes. Iron is involved in the maintenance of circadian period length in Arabidopsis. Global transcriptome analysis reveals circadian regulation of key pathways in plant growth and development.
Effects of abiotic stress on plants: Natural strategies for photosynthetic light harvesting. A compact model for the complex plant circadian clock. A circadian pacemaker in free-living chipmunks: Natural diversity in daily rhythms of gene expression contributes to phenotypic variation. Into the fourth dimension - The influence of time on the drought response of Brassica rapa, an agriculturally important species of plant, has been clarified. Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage. Circadian control of global gene expression patterns.
Balance equations can buffer noisy and sustained environmental perturbations of circadian clocks.
Regulation of Circadian Clocks by Redox Homeostasis
Interface Focus 1 — The ELF4 gene controls circadian rhythms and flowering time in Arabidopsis thaliana. Peroxiredoxins are conserved markers of circadian rhythms. Quantitative variation in water-use efficiency across watering regimes and its relationship with circadian, vegetative, reproductive, and leaf gas-exchange traits.
The genetic architecture of ecophysiological and circadian traits in Brassica rapa. ROS signaling pathways in chilling stress. Global profiling of rice and poplar transcriptomes highlights key conserved circadian-controlled pathways and cis-regulatory modules.
Stress memory and the inevitable effects of drought: The rhythms of life: Post-translational modifications regulate the ticking of the circadian clock. Integration of metabolite with transcript and enzyme activity profiling during diurnal cycles in Arabidopsis rosettes. Reactive oxygen species and antioxidant machinery in abiotic stress tolerance in crop plants. A tidal wave of signals: Starch and the clock: Circadian rhythms confer a higher level of fitness to Arabidopsis plants. Temporal network analysis identifies early physiological and transcriptomic indicators of mild drought in Brassica rapa.
Integrating circadian dynamics with physiological processes in plants. Circadian regulation of abiotic stress tolerance in plants. Using membrane failure and chlorophyll a fluorescence to predict plant mortality from drought. Stochastic models of cellular circadian rhythms in plants help to understand the impact of noise on robustness and clock structure. Stochastic properties of the plant circadian clock. Systems approach identifies an organic nitrogen-responsive gene network that is regulated by the master clock control gene CCA1. Interconnections of reactive oxygen species homeostasis and circadian rhythm in Neurospora crassa.
Multiple phytohormones influence distinct parameters of the plant circadian clock.
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Genes Cells 11 — The circadian system in higher plants. Photosynthetic entrainment of the Arabidopsis thaliana circadian clock. Modulation of environmental responses of plants by circadian clocks. Oxidation-reduction cycles of peroxiredoxin proteins and non-transcriptional aspects of timekeeping. The plant circadian clock influences rhizosphere community structure and function. Correlations between circadian rhythms and growth in challenging environments. Towards understanding extracellular ROS sensory and signaling systems in plants.
A key unanswered question is what determines Prx oscillations. Srx, which reduces the inactive sulfinic acid form into the active sulfenic acid form, might indeed account for these oscillations. However, some organisms that display oscillations in Prx do not express Srx homologs i. Given the highly conserved redox component of circadian oscillations, it is an important goal to now understand the relationship between the classical TTFL and Prx oscillations Interestingly, when the transcriptional machinery is disrupted e.
Along the same lines, when the Prx clock system is abolished, as occurs in mutants of S. Taken together, these studies show that TTFL and Prx cycles are intertwined but potentially autonomous components of the circadian system. These results also raise the possibility that the redox status of the cell fluctuates and that these oscillations have critical and as yet incompletely understood biological consequences. Initial hints that redox metabolism might be linked to the circadian clock were provided by work done by Rutter et al. However, these studies were purely biochemical, based solely on the use of purified recombinant proteins, and used concentrations of reactants much higher than is seen physiologically, making their wider interpretation difficult, especially in an in vivo context.
This study demonstrated that the redox state of SCN oscillates in a self-sustained fashion and that these oscillations contribute to determining the excitability of SCN neurons via non-transcriptional regulation of potassium channels. However, the connection between the transcriptional clock and redox oscillations in this tissue requires further investigation.
Whether redox fluctuations are an output of circadian rhythms or whether they can act as input, or indeed both, is still under intense investigation. In favor of a mechanistic link between redox fluctuations and the regulation of gene expression, studies in zebrafish demonstrated that changes in redox state actively control the expression of light-dependent genes.
Light, which is the key entraining stimulus in this organism, generates H 2 O 2 , which in turn regulates the expression of the clock genes zCry1 and zPer2. Interestingly, oscillations in the mRNA levels of these genes are paralleled by antiphasic oscillations in mRNA and the activity of catalase 42 , suggesting that this enzyme is involved in the control of H 2 O 2 -mediated circadian gene expression.
Recently, LdpA l ight- d ependent p eriod A , a component of the cyanobacterial circadian clock, was proposed to act as a redox sensor and to be used by the clock to adjust the period length LdpA contains iron-sulfur centers and can sense the redox state of the cell, which correlates with the amount of light high light correlates with a reduced redox state, whereas low light is associated with an oxidized redox state.
Interestingly, on the basis of the light conditions, LdpA modulates the levels of CikA and KaiA, the latter of which is a key component of the central oscillator 44 , thereby affecting the period length. Furthermore, cyanobacteria exposed to high light conditions show short periods, whereas cyanobacteria exposed to low light conditions display long periods.
Finally, the effects of altered ROS and the circadian clock have also been observed in N. These results clearly show that fluctuations in the redox state of the cells have an impact on the expression of clock-related genes in multiple diverse systems. This scenario is further complicated by the finding that clock genes can in turn regulate the expression of antioxidant enzymes, thus providing an important and novel feedback loop Fig. For instance, in A. Importantly, mutations in the core clock regulator CCA1 c ircadian c lock- a ssociated 1 or in other components of the TTFL affect this time of the day specific pattern.
In addition, it was observed that ROS can feed back to affect the transcription of clock-regulated genes. The importance of this cross-talk has been underlined in Drosophila melanogaster , in which the per gene has been shown to be essential for maintaining antioxidant defense. Indeed, flies exposed to H 2 O 2 show daily mortality rhythms and are more susceptible during the late light phase.
Mutation in the per gene abolishes this time of the day sensitivity and renders flies more susceptible to oxidative stress in general This impairment in ROS homeostasis correlates with early aging and age-dependent pathologies. These data again suggest a connection between the circadian clock and redox homeostasis More recently, the circadian system has been shown to also modulate the pathways involved in production and utilization of GSH Importantly, mutants lacking the clock genes per and cyc show no rhythms in the expression of these proteins, underlying the link between GSH metabolism and the circadian system.
Cross-talk between the circadian clock and redox homeostasis. The circadian clock and the redox state of the cell are interconnected. The expression level and activity of antioxidant enzymes determine the levels of intracellular ROS, which have been shown to impinge on the expression pattern of clock genes. In addition, some antioxidant enzymes have been shown to follow a circadian pattern of expression, suggesting that the clock system can regulate redox homeostasis. An emerging feature of redox signaling is its spatial and temporal compartmentalization.
Recent developments highlight that different ROS signaling and redox buffering systems are spatially segregated and can have unique compartmentalized functions Fig. For example, pools of mitochondrial, cytosolic, and nuclear GSH are separated within cells, and the trafficking of GSH, from the cytosol to the mitochondrial intramembrane space, is tightly regulated by porins in their membranes Importantly, the maintenance of localized redox states is critical for cell function.
Mitochondria-specific depletion of GSH makes mitochondria more sensitive to oxidative damage 57 , whereas overexpression of the mitochondrial glutaredoxin Grx2 protects against oxidative stress to prevent apoptosis Compartmentalization of redox systems. Redox systems are compartmentalized, and pools of antioxidant enzymes are distributed differently in the cell.
Pools of GSH and Trx have been described in the cytosolic, mitochondrial, and nuclear compartments. The nuclear translocation of Nrf2 is regulated by a redox switch controlled by GSH and Keap1 oxidation, whereas its DNA-binding activity is regulated by a nuclear pool of Trx1. Although evidence suggests that ROS are bona fide signaling molecules, some skepticism has been raised because of their high reactivity and low substrate specificity. However, there is evidence of tight coupling of ROS generators to the activity of antioxidant buffering systems and to specific targets, which would explain how the specificity of ROS signaling is brought about 62 — In the adrenal gland, for example, H 2 O 2 is involved in a feedback control loop to regulate corticosteroid synthesis In the last phase of adrenocorticotropic hormone-induced steroidogenesis, cholesterol is imported in mitochondria, where cytochrome P enzymes catalyze the oxidative cleavage of its side chain.
As a byproduct of their activity, cytochromes generate H 2 O 2 , which is eliminated by Prx3. During the catalytic cycle, Prx3 can occasionally be inactivated by hyperoxidation. Its activity is normally reverted by Srx. However, when corticosteroid synthesis increases, so does H 2 O 2 , and Srx activity is no longer sufficient to reduce and reactivate Prx3. This causes a further increase in H 2 O 2 levels and the overflow of H 2 O 2 in the cytosol. This last event triggers a signaling cascade involving p38 MAPK, which eventually inhibits corticosteroid synthesis.
In addition, tissue-specific ablation of Srx results in suppression of the adrenal circadian rhythms of corticosterone production, suggesting that Prx hyperoxidation, corticosteroid synthesis, and the circadian clock are interconnected. Interestingly, oxidative signals can cause selective oxidation of specific redox couples. Furthermore, one of the major transcription factors activated by oxidative stress, Nrf2 can be differentially activated by redox signals: It is tempting to speculate that different redox systems are strategically located within the cell not only to protect substrates from excessive oxidation but also to regulate specific signaling pathways.
In addition, different redox couples might act in concert to specifically modulate the response to ROS signals in proximity of key redox-sensitive proteins. Determining how this compartmentalized nature of cellular redox systems links to the clockwork will be critical to fully understand how the cell en masse keeps daily time. We believe that this will be an exciting area of investigation in the next few years.
Substantial evidence highlights the capability of living organisms to resonate with environmental cycles, which confers an evolutionary advantage because perturbing the clockwork reduces fitness. However, the biological mechanisms underlying the regulation of circadian rhythms are still elusive in the light of new insights coming from redox biology.
It now appears that control of ROS signaling is deeply intertwined in the circadian clock system. Disruption of circadian rhythms in humans has been linked to several diseases such as breast cancer, obesity, diabetes, sleep disorders, and neurodegenerative diseases Given the role of ROS in human pathophysiology, it is tempting to speculate that some of the pathologies associated with the deregulation of clock signaling are partially caused by alteration in redox signaling and possibly their compartmentalized nature.
Thus, we propose that the understanding of how localized ROS production affects the activity of oscillators within cells will have important consequences for the development of dedicated therapies aimed at restoring aberrant signaling. You'll be in good company.