Reactive oxygen species (ROS) are known as toxic metabolic products in plants and other aerobic organisms. An elaborate and highly redundant plant ROS network, composed of antioxidant enzymes, antioxidants and ROS-producing enzymes, is responsible for maintaining ROS levels under tight control. This allows ROS to serve as signaling molecules that coordinate an astonishing range of diverse plant processes. The specificity of the biological response to ROS depends on the chemical identity of ROS, intensity of the signal, sites (...) of production, plant developmental stage, previous stresses encountered and interactions with other signaling molecules such as nitric oxide, lipid messengers and plant hormones. Although many components of the ROS signaling network have recently been identified, the challenge remains to understand how ROS-derived signals are integrated to eventually regulate such biological processes as plant growth, development, stress adaptation and programmed cell death. (shrink)

Reactive oxygen species (ROS) are highly reactive molecules produced in cells. So far, they have mostly been connected to diseases and pathological conditions. More recent results revealed a somewhat unexpected role of ROS in control of developmental processes. In this review, we elaborate on ROS in development, focussing on their connection to epithelial tissue morphogenesis. After briefly summarising unique characteristics of epithelial cells, we present some characteristic features of ROS species, their production and targets, with (...) a focus on proteins important for epithelial development and function. Finally, we provide examples of regulation of epithelial morphogenesis by ROS, and also of developmental genes that regulate the overall redox status. We conclude by discussing future avenues of research that will further elucidate ROS regulation in epithelial development. (shrink)

Although the generation of reactive oxygen species is an activity normally associated with phagocytic leucocytes, mammalian spermatozoa were, in fact, the first cell type in which this activity was described. In recent years it has become apparent that spermatozoa are not the only nonphagocytic cells to exhibit a capacity for reactive oxygen species production, because this activity has been detected in a wide variety of different cells including fibroblasts, mesangial cells, oocytes, Leyding cells endothelial (...) cells, thryroid cells, adipocytes, tumour cell and platelets. Since the capacity to generate reactive oxygen species is apparently so widespread, the risk‐benefit equation for these potentially pernicious molecules becomes a matter of intese interest. In the case of human spermatozoa, the risk of manufacturing reactive oxygen metabolites is considerable because these cells are particularly vulnerable to lipid peroxidation. Indeed, there is now good evidence to indicate that oxygen radicals are involved in the initiation of peroxidative damage to the sperm plasma membrane, seen in many cases of male infertility. This risk is off‐set by recent data suggesting that superoxide anions and hydrogen peroxide also participate in the induction of key biological events such as hyperactiavated motility and the acrosome reaction. Thus, human spermatozoa appear to use reactive oxygen species for a physiological purpose and have the difficult task of ensuring the balanced generation of these potentially harmful, but biologically important, modulators of cellular function. (shrink)

Introduction of O2 to Earth's early biosphere stimulated remarkable evolutionary adaptations, and a wide range of electron acceptors allowed diverse, energy-yielding metabolic pathways. Enzymatic reduction of O2 yielded a several-fold increase in energy production, enabling evolution of multi-cellular animal life. However, utilization of O2 also presented major challenges as O2 and many of its derived reactive oxygen species are highly toxic, possibly impeding multicellular evolution after the Great Oxidation Event. Remarkably, ROS, and especially hydrogen peroxide, seem to (...) play a major part in early diversification and further development of cellular respiration and other oxygenic pathways, thus becoming an intricate part of evolution of complex life. Hence, although harnessing of chemical and thermo-dynamic properties of O2 for aerobic metabolism is generally considered to be an evolutionary milestone, the ability to use ROS for cell signaling and regulation may have been the first true breakthrough in development of complex life. The importance of Earth's oxygen cycle and reactive oxygen species produced on the evolution of complex life. The ability to detoxify oxygen species is not a trait that emerged as a response to increased O2 levels but rather crucial adaptation to the early Earth's weakly oxic microenvironments. (shrink)

It has been assumed that at the whole organismal level, the mitochondrial reactive oxygen species (ROS) production is proportional to the oxygen consumption. Recently, a number of researchers have challenged this assumption, based on the observation that the ROS production per unit oxygen consumed in the resting state of mitochondrial respiration is much higher than that in the active state. Here, we develop a simple model to investigate the validity of the assumption and the challenge (...) of it. The model highlights the significance of the time budget that mitochondria operate in the different respiration states. The model suggests that under three physiologically possible conditions, the difference in ROS production per unit oxygen consumed between the respiration states does not upset the proportionality between the whole animal ROS production and oxygen consumption. The model also shows that mitochondrial uncoupling generally enhances the proportionality. (shrink)

Oxygen is a key regulator of both development and homeostasis and a promising candidate to bridge the influence of the environment and the evolution of new traits. To clarify the various ways in which oxygen may modulate embryogenesis, its effects are reviewed at distinct organizational levels. First, the role of pathways that sense dioxygen levels and reactive oxygen species are reviewed. Then, the effects of microenvironmental oxygen on metabolism, stemness, and differentiation throughout embryogenesis are (...) discussed. Last, the interplay between ecology and development are reexamined with a focus on the evolution of tetrapods, including during the emergence of a novel mechanism that shapes amniote limbs—interdigital cell death. Both genetic and environmental components work together during the formation of organisms, highlighting the importance of a multidisciplinary approach for understanding the evolution of new traits. (shrink)

Precision cell signaling activities of reactive electrophilic species (RES) are arguably among the most poorly‐understood means to transmit biological messages. Latest research implicates native RES to be a chemically‐distinct subset of endogenous redox signals that influence cell decision making through non‐enzyme‐assisted modifications of specific proteins. Yet, fundamental questions remain regarding the role of RES as bona fide second messengers. Here, we lay out three sets of criteria we feel need to be met for RES to be considered as (...) true cellular signals that directly mediate information transfer by modifying “first‐responding” sensor proteins. We critically assess the available evidence and define the extent to which each criterion has been fulfilled. Finally, we offer some ideas on the future trajectories of the electrophile signaling field taking inspiration from work that has been done to understand canonical signaling mediators. (shrink)

What kind of symbiosis between archaeon and bacterium gave rise to their eventual merger at the origin of the eukaryotes? I hypothesize that conditions favouring bacterial uptake were based on exchange of intermediate carbohydrate metabolites required by recurring changes in availability and use of the two different terminal electron chain acceptors, the bacterial one being oxygen. Oxygen won, and definitive loss of the archaeal membrane potential allowed permanent establishment of the bacterial partner as the proto‐mitochondrion, further metabolic integration (...) and highly efficient ATP production. This represents initial symbiogenesis, when crucial eukaryotic traits arose in response to the archaeon‐bacterium merger. The attendant generation of internal reactive oxygen species (ROS) gave rise to a myriad of further eukaryotic adaptations, such as extreme mitochondrial genome reduction, nuclei, peroxisomes and meiotic sex. Eukaryotic origins could have started with shuffling intermediate metabolites as is still essential today. (shrink)

A major obstacel to the study of mammalian development, and to the practical application of knowledge gained from it in the clinic during therapeutic in vitro fertilisation and embryo transfer (IVF‐ET), is the propensity of embryos to become retarded or arrested during their culture in vitro. The precise developmental cell cycle in which embryos arrest or delay is characteristic for the species and coincides with the earliest period of embryonic gene expression. Much evidence reviewed here implicates free oxygen (...) radicals (FORs) in the process of arrest. Thus, studies on the development of mouse preimplantation embryos in vitro have shown that (i) FORs are elevated in vitro, but not in vivo, at the time at which embryos become arrested or delayed, (ii) systems for removing reactive oxygen species to limit the formation of hydroxy radicals are present, although they have not yet been assessed quantitatively and may differ qualitatively from those in adult cells, (iii) metabolic and possibly genetic adaptations to oxidative damage are evident, (iv) published procedures for overcoming in vitro arrest are explicable in terms of FOR‐mediated damage or responses and (v) the arrest or delay of most embryos in vitro can be reduced or prevented experimentally by addition of metal chelators to limit hydroxy radical formation and lipid hydroperoxidation. (shrink)

RubisCO is Earth's main enzyme responsible for CO2 fixation via carboxylation of ribulose-1,5-bisphosphate into organic matter. Besides the carboxylation reaction, RubisCO also catalyzes the oxygenation of RuBP by O2, which is probably as old as its carboxylation properties. Based on molecular phylogeny, the occurrence of the reactive oxygen species -removing system and kinetic properties of different RubisCO forms, we postulated that RubisCO oxygenase activity appeared in local microoxic areas, yet before the appearance of oxygenic photosynthesis. Here, in (...) reviewing the literature, we present a novel hypothesis: the RubisCO early oxygenase activity hypothesis. This hypothesis may be compared with the exaptation hypothesis, according to which latent RubisCO oxygenase properties emerged later during the oxygenation of the Earth's atmosphere. The reconstruction of ancestral RubisCO forms using ancestral sequence reconstruction techniques, as a promising way for testing of RubisCO early oxygenase activity hypothesis, is presented. RubisCO catalyzes carboxylation and oxygenation of ribulose-1,5-bisphosphate. Carboxylating properties of RubisCO are an ancient way for CO2 fixation into organic matter. However, an evolutionary importance of oxygenase activity of RubisCO remains enigmatic. Here, we formulated RubisCO early oxygenase activity hypothesis. According to this hypothesis, RubisCO oxygenase activity appeared yet before the appearance of oxygenic photosynthesis. (shrink)

Rho GTPases are critically important and are centrally positioned regulators of the actomyosin cytoskeleton. By influencing the organization and architecture of the cytoskeleton, Rho proteins play prominent roles in many cellular processes including adhesion, migration, intra‐cellular transportation, and proliferation. The most important method of Rho GTPase regulation is via the GTPase cycle; however, post‐translational modifications (PTMs) also play critical roles in Rho protein regulation. Relative to other PTMs such as lipidation or phosphorylation that have been extensively characterized, protein oxidation is (...) a regulatory PTM that has been poorly studied. Protein oxidation primarily occurs from the reaction of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), with amino acid side chain thiols on cysteine (Cys) and methionine (Met) residues. The versatile redox modifications of cysteine residues exemplify their integral role in cell signalling processes. Here we review prominent members of the Rho GTPase family and discuss how lipidation, phosphorylation, and oxidation on conserved cysteine residues affects their regulation and function. (shrink)

Recently, we reported that melanoma risk in redheads is linked not only to pale skin, but also to the synthesis of the pigment – called pheomelanin – that gives red hair its color. We demonstrated that pheomelanin synthesis is associated with increased oxidative stress in the skin, yet we have not uncovered the chemical pathway between the molecule pheomelanin and the DNA damage that drives melanoma formation. Here, we hypothesize two possible pathways. On one hand, pheomelanin might generate reactive (...) oxygen species (ROS) that directly or indirectly cause oxidative DNA damage. On the other hand, pheomelanin synthesis might consume cellular antioxidant stores and make the cell nucleus more vulnerable to other endogenous ROS. Uncovering the mechanistic pathway between pheomelanin and oxidative DNA damage will be an important step in developing strategies to lower melanoma risk in redheads. (shrink)

The mitochondrion is known as the “powerhouse” of eukaryotic cells since it is the main site of adenosine 5′‐triphosphate (ATP) production. Using a temperature‐sensitive fluorescent probe, it has recently been suggested that the stray free energy, not captured into ATP, is potentially sufficient to sustain mitochondrial temperatures higher than the cellular environment, possibly reaching up to 50 °C. By 50 °C, some DNA and mitochondrial proteins may reach their melting temperatures; how then do these biomolecules maintain their structure and function? (...) Further, the production of reactive oxygen species (ROS) accelerates with temperature, implying higher oxidative stresses in the mitochondrion than generally appreciated. Herein, it is proposed that mitochondrial heat shock proteins (particularly Hsp70), in addition to their roles in protein transport and folding, protect mitochondrial proteins and DNA from thermal and ROS damage. Other thermoprotectant mechanisms are also discussed. (shrink)

Mitochondrial respiration is the predominant source of ATP. Excessive rates of electron transport cause a higher production of harmful reactive oxygen species (ROS). There are two regulatory mechanisms known. The first, according to Mitchel, is dependent on the mitochondrial membrane potential that drives ATP synthase for ATP production, and the second, the Kadenbach mechanism, is focussed on the binding of ATP to Cytochrome c Oxidase (CytOx) at high ATP/ADP ratios, which results in an allosteric conformational change to (...) CytOx, causing inhibition. In times of stress, ATP‐dependent inhibition is switched off and the activity of CytOx is exclusively determined by the membrane potential, leading to an increase in ROS production. The second mechanism for respiratory control depends on the quantity of electron transfer to the Heme aa3 of CytOx. When ATP is bound to CytOx the enzyme is inhibited, and ROS formation is decreased, although the mitochondrial membrane potential is increased. (shrink)

As free‐living organisms, alpha‐proteobacteria produce reactive oxygen species (ROS) that diffuse into the surroundings; once constrained inside the archaeal ancestor of eukaryotes, however, ROS production presented evolutionary pressures – especially because the alpha‐proteobacterial symbiont made more ROS, from a variety of substrates. I previously proposed that ratios of electrons coming from FADH2 and NADH (F/N ratios) correlate with ROS production levels during respiration, glucose breakdown having a much lower F/N ratio than longer fatty acid (FA) breakdown. Evidently, (...) higher endogenous ROS formation did not hinder eukaryotic evolution, so how were its disadvantages mitigated? I propose that the resulting selection pressures favoured the evolution of a variety of eukaryotic ‘innovations’: peroxisomes for FA breakdown, carnitine shuttles, the linkage of beta‐oxidation to antioxidant properties, uncoupling proteins (UCPs) and using mitochondrial uncoupling during beta‐oxidation to reduce ROS. Recently observed relationships between peroxisomes and mitochondria further support the model. (shrink)

It is not clear why cancer cells choose to disrupt their circadian clock rhythms, and whether such disruption governs a selective fitness and a survival advantage. In this review, I focus on understanding the impacts of clock gene disruption on a simpler model, such as the unicellular cyanobacterium, in order to explain how cancer cells may alter the circadian rhythm to reprogram their metabolism based on their needs and status. It appears to be that the activation of the oxidative pentose (...) phosphate pathway (OPPP) and production of NADPH, the preferred molecule for detoxification of reactive oxygen species, is a critical process for night survival in unicellular organisms. The circadian clock acts as a gatekeeper that controls how the organism will utilize its sugar, shifting sugar influx between glycolysis and OPPP. The circadian clock can thus act as a gatekeeper between an anabolic, proliferative mode and a homeostatic, survival mode. (shrink)

The environment can elicit biological responses such as oxidative stress (OS) and inflammation as a consequence of chemical, physical, or psychological changes. As population studies are essential for establishing these environment-organism interactions, biomarkers of OS or inflammation are critical in formulating mechanistic hypotheses. By using examples of stress induced by various mechanisms, we focus on the biomarkers that have been used to assess OS and inflammation in these conditions. We discuss the difference between biomarkers that are the result of a (...) chemical reaction (such as lipid peroxides or oxidized proteins that are a result of the reaction of molecules with reactive oxygen species) and those that represent the biological response to stress, such as the transcription factor NRF2 or inflammation and inflammatory cytokines. The high-throughput and holistic approaches to biomarker discovery used extensively in large-scale molecular epidemiological exposome are also discussed in the context of human exposure to environmental stressors. We propose to consider the role of biomarkers as signs and to distinguish between signs that are just indicators of biological processes and proxies that one can interact with and modify the disease process. (shrink)

The theory stating that oxidative stress is at the root of several diseases is extremely popular. However, so far, no antioxidant is recommended or offered by healthcare systems neither approved as therapy by regulatory agencies that base their decisions on evidence-based medicine. This is simply because, so far, despite many preclinical and clinical studies indicating a beneficial effect of antioxidants in many disease conditions, randomised clinical trials have failed to provide the evidence of efficacy required for drug approval. In this (...) review, we discuss the levels of evidence required to claim causality in preclinical research on OS, the weakness of the oversimplification associated with OS theory of disease and the importance of the narrative in its popularity. Finally, from a more translational perspective, we discuss the reasons why antioxidants acting by scavenging reactive oxygen species might not only prevent their detrimental effects but also interfere with essential signalling roles. We propose that ROS have a complex metabolism and are generated by different enzymes at diverse sites and with different timing. Aggregating this plurality of systems in a single theory of disease may not be the best way to develop new drugs, and future research may need to focus on specific oxygen-toxifying pathways rather than on non-specific ROS scavengers. Finally, similarly to what is nowadays required for clinical trials, we recommend making unpublished data available in repositories, as this will allow big data approaches or meta-analyses without the blinders of the publication bias. (shrink)

Beta‐oxidation of fatty acids and detoxification of reactive oxygen species are generally accepted as being fundamental functions of peroxisomes. Additionally, these pathways might have been the driving force favoring the selection of this compartment during eukaryotic evolution. Here we performed phylogenetic analyses of enzymes involved in beta‐oxidation of fatty acids in Bacteria, Eukaryota, and Archaea. These imply an alpha‐proteobacterial origin for three out of four enzymes. By integrating the enzymes' history into the contrasting models on the origin (...) of eukaryotic cells, we conclude that peroxisomes most likely evolved non‐symbiotically and subsequent to the acquisition of mitochondria in an archaeal host cell. (shrink)

Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead has been shown to elevate the Alzheimer's disease related beta-amyloid peptide , which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2'-deoxyguanosine levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase in rats developmentally exposed to Pb. Oxo8dG was transiently modulated early in life , but was later elevated 20 months after (...) exposure to Pb had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase , manganese-SOD , and reduced-form glutathion . These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances. (shrink)

Akt, a protein kinase hyperactivated in many tumors, plays a major role in both cell survival and resistance to tumor therapy. A recent study,1 along with other evidences, shows interestingly, that Akt is not a single‐function kinase, but may facilitate rather than inhibit cell death under certain conditions. This hitherto undetected function of Akt is accomplished by its ability to increase reactive oxygen species and to suppress antioxidant enzymes. The ability of Akt to down‐regulate antioxidant defenses uncovers (...) a novel Achilles' heel, which could be exploited by oxidant therapies in order to selectively eradicate tumor cells that express high levels of Akt activity. (shrink)

Aspects of peroxisome evolution, uncoupling, carnitine shuttles, supercomplex formation, and missing neuronal fatty acid oxidation (FAO) are linked to reactive oxygen species (ROS) formation in respiratory chains. Oxidation of substrates with high FADH2/NADH (F/N) ratios (e.g., FAs) initiate ROS formation in Complex I due to insufficient availability of its electron acceptor (Q) and reverse electron transport from QH2, e.g., during FAO or glycerol‐3‐phosphate shuttle use. Here it is proposed that the Q‐cycle of Complex III contributes to enhanced (...) ROS formation going from low F/N ratio substrates (glucose) to high F/N substrates. This contribution is twofold: 1) Complex III uses Q as substrate, thus also competing with Complex I; 2) Complex III itself will produce more ROS under these conditions. I link this scenario to the universally observed Complex III dimerization. The Q‐cycle of Complex III thus again illustrates the tension between efficient ATP generation and endogenous ROS formation. This model can explain recent findings concerning succinate and ROS‐induced uncoupling. (shrink)

Recently, the group of McBride reported a stunning observation regarding peroxisome biogenesis: newly born peroxisomes are hybrids of mitochondrial and ER-derived pre-peroxisomes. What was stunning? Studies performed with the yeast Saccharomyces cerevisiae had convincingly shown that peroxisomes are ER-derived, without indications for mitochondrial involvement. However, the recent finding using fibroblasts dovetails nicely with a mechanism inferred to be driving the eukaryotic invention of peroxisomes: reduction of mitochondrial reactive oxygen species generation associated with fatty acid oxidation. This not (...) only explains the mitochondrial involvement, but also its apparent absence in yeast. The latest results allow a reconstruction of the evolution of the yeast's highly derived metabolism and its limitations as a model organism in this instance. As I review here, peroxisomes are eukaryotic inventions reflecting mutual host endosymbiont adaptations: this is predicted by symbiogenetic theory, which states that the defining eukaryotic characteristics evolved as a result of mutual adaptations of two merging prokaryotes. See also the video abstract here: https://youtu.be/HtyKhQ3DSxg Eukaryotic peroxisomes illustrate effects of symbiogenesis, following the non-phagocytotic merger of an archaeon and a bacterium. Internal ROS formation upon fatty acid oxidation was reduced by the invention of peroxisomes for extra-mitochondrial FA oxidation. Both peroxisomal membranes and their oldest enzymes seem ultimately derived from the pre-mitochondrion. (shrink)

The standard representation of the Central Dogma (CD) of Molecular Biology conspicuously ignores metabolism. However, both the metabolites and the biochemical fluxes behind any biological phenomenon are encrypted in the DNA sequence. Metabolism constrains and even changes the information flow when the DNA‐encoded instructions conflict with the homeostasis of the biochemical network. Inspection of adaptive virulence programs and emergence of xenobiotic‐biodegradation pathways in environmental bacteria suggest that their main evolutionary drive is the expansion of their metabolic networks towards new chemical (...) landscapes rather than perpetuation and spreading of their DNA sequences. Faulty enzymatic reactions on suboptimal substrates often produce reactive oxygen species (ROS), a process that fosters DNA diversification and ultimately couples catabolism of the new chemicals to growth. All this calls for a revision of the CD in which metabolism (rather than DNA) has the leading role. (shrink)

The continuing viability of the free‐radical theory of ageing has been questioned following apparently incompatible recent results. We show by modelling positional effects of the generation and primary targets of reactive oxygen species that many of the apparently negative results are likely to be misleading. We conclude that there is instead a need to look more closely at the mechanisms by which free radicals contribute to age‐related dysfunction in living systems. There also needs to be deeper understanding (...) of the dynamics of accumulation and removal of the various kinds of molecular damage, in particular mtDNA mutations. Finally, the expectation that free‐radical damage on its own might cause ageing needs to be relinquished in favour of the recognition that the free‐radical theory is just one of the multiple mechanisms driving the ageing process. (shrink)

Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity (...) of protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age‐related diseases associated with impaired autophagy and oxidative stress. (shrink)

Arbuscular mycorrhizal fungi are considered as a potential biotechnological tool for improving phytostabilization efficiency and plant tolerance to heavy metal-contaminated soils. However, the mechanisms through which AMF help to alleviate metal toxicity in plants are still poorly understood. A greenhouse experiment was conducted to evaluate the effects of two AMF species on the growth, Pb accumulation, photosynthesis and antioxidant enzyme activities of a leguminous tree at Pb addition levels of 0, 500, 1000 and 2000 mg kg-1 soil. AMF symbiosis (...) decreased Pb concentrations in the leaves and promoted the accumulation of biomass as well as photosynthetic pigment contents. Mycorrhizal plants had higher gas exchange capacity, non-photochemistry efficiency, and photochemistry efficiency compared with non-mycorrhizal plants. The enzymatic activities of superoxide dismutase, ascorbate peroxidases and glutathione peroxidase were enhanced, and hydrogen peroxide and malondialdehyde contents were reduced in mycorrhizal plants. These findings suggested that AMF symbiosis could protect plants by alleviating cellular oxidative damage in response to Pb stress. Furthermore, mycorrhizal dependency on plants increased with increasing Pb stress levels, indicating that AMF inoculation likely played a more important role in plant Pb tolerance in heavily contaminated soils. Overall, both F. mosseae and R. intraradices were able to maintain efficient symbiosis with R. pseudoacacia in Pb polluted soils. AMF symbiosis can improve photosynthesis and reactive oxygen species scavenging capabilities and decrease Pb concentrations in leaves to alleviate Pb toxicity in R. pseudoacacia. Our results suggest that the application of the two AMF species associated with R. pseudoacacia could be a promising strategy for enhancing the phytostabilization efficiency of Pb contaminated soils. (shrink)

Mitochondrial dysfunction has long been considered a key mechanism in the ageing process but surprisingly little attention has been paid to the impact of mitochondrial number or density within cells. Recent reports suggest a positive association between mitochondrial density, energy homeostasis and longevity. However, mitochondrial number also determines the number of sites generating reactive oxygen species (ROS) and we suggest that the links between mitochondrial density and ageing are more complex, potentially acting in both directions. The idea (...) that increased density, especially when combined with mitochondrial dysfunction, might accelerate ageing is supported by a negative correlation between mitochondrial density and maximum longevity in an interspecies comparison in mammals, and by evidence for an intimate interconnection between cellular ROS levels, mitochondrial density and cellular ageing. Recent data suggest that retrograde response, which activates mitochondrial biogenesis, accompanies cellular ageing processes. We hypothesise that increased mitochondrial biogenesis, and possibly also impaired degradation and segregation of mitochondria, if occurring as adaptation to pre‐existing mitochondrial dysfunction, might aggravate ROS production and thus actively contribute to ageing. BioEssays 29:908–917, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Coral bleaching has attracted considerable study, yet one central question remains unanswered: given that corals and their Symbiodinium symbionts have co‐evolved for millions of years, why does this clearly maladaptive process occur? Bleaching may result from evolutionary conflict between the host corals and their symbionts. Selection at the level of the individual symbiont favors using the products of photosynthesis for selfish replication, while selection at the higher level favors using these products for growth of the entire host/symbiont community. To hold (...) the selfish lower‐level units in check, mechanisms of conflict mediation must evolve. Fundamental features of photosynthesis have been co‐opted into conflict mediation so that symbionts that fail to export these products produce high levels of reactive oxygen species and undergo programmed cell death. These mechanisms function very well under most environmental conditions, but under conditions particularly detrimental to photosynthesis, it is these mechanisms of conflict mediation that trigger bleaching. (shrink)

Ferroptosis, a form of regulated cell death triggered by lipid hydroperoxide accumulation, has an important role in a variety of diseases and pathological conditions, such as cancer. Targeting ferroptosis is emerging as a promising means of therapeutic intervention in cancer treatment. Polyunsaturated fatty acids, reactive oxygen species, and labile iron constitute the major underlying triggers for ferroptosis. Other regulators of ferroptosis have also been discovered recently, among them the mechanistic target of rapamycin complex 1 (mTORC1), a central (...) controller of cell growth and metabolism. Inhibitors of mTORC1 have been used in treating diverse diseases, including cancer. In this review, we discuss recent findings linking mTORC1 to ferroptosis, dissect mechanisms underlying the establishment of mTORC1 as a key ferroptosis modulator, and highlight the potential of co‐targeting mTORC1 and ferroptosis in cancer treatment. This review will provide valuable insights for future investigations of ferroptosis and mTORC1 in fundamental biology and cancer therapy. (shrink)

Previous studies have shown that zinc deficiency leads to apoptosis of neuronal precursor cells in vivo and in vitro. In addition to the role of p53 as a nuclear transcription factor in zinc deficient cultured human neuronal precursors (NT-2), we have now identified the translocation of phosphorylated p53 to the mitochondria and p53-dependent increases in the pro-apoptotic mitochondrial protein BAX leading to a loss of mitochondrial membrane potential as demonstrated by a 25% decrease in JC-1 red:green fluorescence ratio. Disruption of (...) mitochondrial membrane integrity was accompanied by efflux of the apoptosis inducing factor (AIF) from the mitochondria and translocation to the nucleus with a significant increase in reactive oxygen species (ROS) after 24 h of zinc deficiency. Measurement of caspase cleavage, mRNA, and treatment with caspase inhibitors revealed the involvement of caspases 2, 3, 6, and 7 in zinc deficiency-mediated apoptosis. Down-stream targets of caspase activation, including the nuclear structure protein lamin and polyADP ribose polymerase (PARP), which participates in DNA repair, were also cleaved. Transfection with a dominant-negative p53 construct and use of the p53 inhibitor, pifithrin- ␮, established that these alterations were largely dependent on p53. Together these data identify a cascade of events involving mitochondrial p53 as well as p53-dependent caspase-mediated mechanisms leading to apoptosis during zinc deficiency. (shrink)

The initial relationships between organisms leading to endosymbiosis and the first eukaryote are currently a topic of hot debate. Here, I present a theory that offers a gradual scenario in which the origins of phagocytosis and mitochondria are intertwined in such a way that the evolution of one would not be possible without the other. In this scenario, the premitochondrial bacterial symbiont became initially associated with a protophagocytic host on the basis of cooperation to kill prey with symbiont‐produced toxins and (...) reactive oxygen species (ROS). Subsequently, the cooperation was focused on the digestion stage, through the acidification of the protophagocytic cavities via exportation of protons produced by the aerobic respiration of the symbiont. The host gained an improved phagocytic capacity and the symbiont received organic compounds from prey. As the host gradually lost its membrane energetics to develop lysosomal digestion, respiration was centralized in the premitochondrial symbiont for energy production for the consortium. (shrink)

All the biological membranes contain oxidoreduction systems actively involved in their bioenergetics. Plasma membrane redox systems seem to be ubiquitous and they have been related to several important functions, including not only their role in cell bioenergetics, but also in cell defense through the generation of reactive oxygen species, in iron uptake, in the control of cell growth and proliferation and in signal transduction. In the last few years, an increasing number of mechanistic and molecular studies have (...) deeply widened our knowledge on the function of these plasma membrane redox systems. The aim of this review is to summarize what is currently known about the components and physiological roles of these systems. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Alzheimer's Disease, Mild Cognitive Impairment, and the Biology of Intrinsic AgingThomas B. L. Kirkwood (bio)Keywordsaging, Alzheimer’s disease, genetic mutation, mild cognitive impairment, telomereThe article by Gaines and Whitehouse (2006) raises key questions about the uncertain relationship between (i) the intrinsic, "normal" aging process, and (ii) the clinicopathologic states represented by the labels of Alzheimer's disease (AD) and mild cognitive impairment (MCI). This short commentary offers a perspective on this (...) debate that is drawn from a consideration of underlying biological mechanisms.Because age is unquestionably the greatest single risk factor associated with AD and MCI, I begin by asking what we know about the intrinsic processes of aging. The central feature of current understanding of intrinsic aging is that it consists of the gradual, lifelong accumulation of a wide variety of molecular and cellular faults that begins very early in life and eventually leads to overt functional impairments resulting in age-related frailty, disability, and disease (Kirkwood 2005). This is an essentially bottom-up process. A strong consensus has emerged in recent years that there is no active program for aging and that there are no genetic factors that have evolved specifically to cause aging or age-related diseases. Unquestionably, there are genes that influence susceptibility to disease and even length of life, but these genes are genes for maintenance and repair functions, not for aging. It is the limitation in the past evolutionary pressure to invest in greater longevity than was required, within an environment where life was usually truncated by hazards such as starvation, injury, or infection, that means that our maintenance systems—good as they are—are insufficient to keep us going indefinitely. Added to this is the idea that there are probably also genes that program processes that are good for the young organism, but which may in later life have harmful effects. Processes like inflammation and apoptosis, which are seen to occur extensively in aged tissues, including brain, surely evolved to help cope with infection and cellular damage arising earlier in life. That they are called into play in aged tissues is a direct, but secondary, consequence of accumulated damage.With this general framework to understand the intrinsic biology of aging, let us now ask what we might expect a priori for the aging of an organ such [End Page 79] as the brain. Although we cannot pretend complete ignorance of how the brain actually does age, our enquiry can be based entirely on data from other organ systems, so we can develop our predictions about brain aging without prejudice.Aging begins very early during human development, faults accumulating from the first stages of embryonic development. Each time a cell divides, each of the daughter cells is likely to acquire a few new mutations. We know this from the estimates for the error rate in DNA replication and the size of the human genome. It is confirmed by direct evidence that at individual gene loci where mutations have been measured, mutation frequency increases with age (Morley 1998; Vijg 2000). In addition to replication errors, DNA is damaged on a daily basis to a very considerable degree by agents such as reactive oxygen species (free radicals), which are formed as byproducts of normal cellular metabolism. Although most of this damage is corrected by repair, the repair mechanisms themselves are not error free and additional mutations accumulate through this route. If a mutation is lethal to the cell, the cell dies and thus the mutation is eliminated. However, the majority of mutations are nonlethal, either because the mutation is recessive and the cell carries an intact gene copy on the other chromosome, because the gene is not currently required, or because the mutation produces only a delayed deleterious effect. Examples of genes that produce delayed deleterious effects include the genes responsible for familial AD. It is interesting to reflect that on statistical grounds alone, it is almost certain that each of us carries a randomly determined fraction of cells in our brains that bear amyloid precursor protein or presenilin mutations associated with AD. We also carry a heterogeneous array of random mutations that compromise essential cell maintenance functions. How many such... (shrink)

In photoreceptors of a dark adapted eye, the inward flux of sodium and calcium ions in the outer segment is balanced by the outward flux of potassium ions. But in the presence of light the creation of cyclic guanosine monophosphate in the outer segment decreases. Due to low concentration of cG the channels in the outer segment open relatively less and thus the influx of calcium ion decreases, leading finally to hyperpolarization of the photoreceptors. We have analyzed theoretically the effect (...) of oxidizing iron ions on the photoreceptors. In order to explain the effects of iron-induced oxidative stress, the different molecules and ions involved in phototransduction are quantified leading to a differential equation for calculating the electroretinogram a-wave voltage. The theoretical results are compared with published experimental data. In the presence of light, the iron ions could push outward the similarly charged calcium ions resulting in a small increase in the amount of inward calcium flux. Again, the presence of iron ions generates Reactive Oxygen Species, and ROS could attract the calcium ions which also increases the calcium flux. This will result in a reduction in the amplitude and slope of the a-wave voltage in the electroretinogram. These results are parametrized in terms of calcium ion concentrations. As the amplitude of the a-wave shows how much electrical signal is produced, its reduction indicates reduction in the visual signal. Thus, the increase in iron ions could explain the reduction in the electrical signal due to iron-induced oxidative stress. (shrink)

CB1 receptors are functionally present within brain mitochondria, although they are usually considered specifically targeted to plasma membrane. Acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. However, the detailed mechanism linking disrupted mitochondrial metabolism and synaptic transmission is still uncharacterized. CB1 receptors are among the most abundant G protein-coupled receptors in the brain and impact on several processes, including fear coping, anxiety, stress, learning, and memory. Mitochondria perform several key physiological processes for neuronal homeostasis, including (...) production of ATP and reactive oxygen species, calcium buffering, metabolism of neurotransmitters, and apoptosis. It is therefore possible that acute activation of mtCB1 impacts on these different mitochondrial functions to modulate synaptic transmission. In reviewing and integrating across the literature in this area, we describe the possible mechanisms involved in the regulation of brain physiology by mtCB1 receptors. Activation of mitochondrial CB1 but not of plasma membrane CB1 decreases brain mitochondrial activity, glutamatergic synaptic transmission, and memory performance. Several processes can be involved in this alteration of brain physiology, including mitochondrial ATP and ROS production, axonal mitochondrial transport, Ca2+ homeostasis, and/or metabolism of the neurotransmitter glutamate. (shrink)

Biomarkers are widely used not only as prognostic or diagnostic indicators, or as surrogate markers of disease in clinical trials, but also to formulate theories of pathogenesis. We identify two problems in the use of biomarkers in mechanistic studies. The first problem arises in the case of multifactorial diseases, where different combinations of multiple causes result in patient heterogeneity. The second problem arises when a pathogenic mediator is difficult to measure. This is the case of the oxidative stress (OS) theory (...) of disease, where the causal components are reactive oxygen species (ROS) that have very short half-lives. In this case, it is usual to measure the traces left by the reaction of ROS with biological molecules, rather than the ROS themselves. Borrowing from the philosophical theories of signs, we look at the different facets of biomarkers and discuss their different value and meaning in multifactorial diseases and system medicine to inform their use in patient stratification in personalized medicine. (shrink)

We recently examined gene expression during Xenopus tadpole tail appendage regeneration and found that carbohydrate regulatory genes were dramatically altered during the regeneration process. In this essay, we speculate that these changes in gene expression play an essential role during regeneration by stimulating the anabolic pathways required for the reconstruction of a new appendage. We hypothesize that during regeneration, cells use leptin, slc2a3, proinsulin, g6pd, hif1α expression, receptor tyrosine kinase (RTK) signaling, and the production of reactive oxygen (...) class='Hi'>species (ROS) to promote glucose entry into glycolysis and the pentose phosphate pathway (PPP), thus stimulating macromolecular biosynthesis. We suggest that this metabolic shift is integral to the appendage regeneration program and that the Xenopus model is a powerful experimental system to further explore this phenomenon.Also watch the Video Abstract. (shrink)

Programmed cell death (PCD) is a process aimed at the removal of redundant, misplaced, or damaged cells and it is essential to the development and maintenance of multicellular organisms. In contrast to the relatively well‐described cell death pathway in animals, often referred to as apoptosis, mechanisms and regulation of plant PCD are still ill‐defined. Several morphological and biochemical similarities between apoptosis and plant PCD have been described, including DNA laddering, caspase‐like proteolytic activity, and cytochrome c release from mitochondria. Reactive (...) oxygen species (ROS) have emerged as important signals in the activation of plant PCD. In addition, several plant hormones may exert their respective effects on plant PCD through the regulation of ROS accumulation. The possible plant PCD regulators discussed in this review are integrated in a model that combines plant‐specific regulators with mechanisms functionally conserved between animals and plants. BioEssays 25:47–57, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

At extreme altitude (>5,000 – 5,500 m), sustained hypoxia threatens human function and survival, and is associated with marked involuntary weight loss (cachexia). This seems to be a coordinated response: appetite and protein synthesis are suppressed, and muscle catabolism promoted. We hypothesise that, rather than simply being pathophysiological dysregulation, this cachexia is protective. Ketone bodies, synthesised during relative starvation, protect tissues such as the brain from reduced oxygen availability by mechanisms including the reduced generation of reactive oxygen (...) species, improved mitochondrial efficiency and activation of the ATP‐sensitive potassium (KATP) channel. Amino acids released from skeletal muscle also protect cells from hypoxia, and may interact synergistically with ketones to offer added protection. We thus propose that weight loss in hypoxia is an adaptive response: the amino acids and ketone bodies made available act not only as metabolic substrates, but as metabolic modulators, protecting cells from the hypoxic challenge.Also watch the Video Abstract. (shrink)

Early in the 20th century, Charles Manning Child attributed organismal gradients in metabolism to interactions among groups of cells. Metabolic gradients are now firmly grounded in redox chemistry, yet modern work on metabolic signaling has consistently focused on the cellular level. Multicellular redox regulation, however, may occur when redox state is determined by the behavior of a group of cells. For instance, typically an abundance of substrate will shift the redox state of mitochondria in the direction of reduction, leading to (...) increased reactive oxygen species (ROS). These ROS, in turn, may modify the conformation and activity of proteins involved in signaling pathways, resulting in phenotypic changes. In contrast, if substrate triggers the contractions of a muscular structure comprising mitochondrion‐rich cells, the resulting metabolic demand may shift the redox state in the direction of oxidation, with a corresponding decrease of ROS and different phenotypic effects. Indeed, colonial hydroids exemplify this process. Parallel examples may occur whenever mitochondria are concentrated in cells of structures that can respond to environmental perturbations with increased metabolic demand. In these circumstances, predicting the direction of metabolic signaling may require an understanding of events at the organismal level. BioEssays 28:72–77, 2006. © 2005 Wiley Periodicals, Inc. (shrink)

Inflammatory mediators have an established role in inducing insulin resistance and promoting hyperglycemia. In turn, hyperglycemia has been argued to drive immune cell dysfunction as a result of mitochondrial dysfunction. Here, the authors review the evidence challenging this view. First, it is pointed out that inflammatory mediators are known to induce altered mitochondrial function. In this regard, critical care patients suffer both an elevated inflammatory tone as well as hyperglycemia, rendering it difficult to distinguish between the effects of inflammation and (...) hyperglycemia. Second, emerging evidence indicates that a decrease in mitochondrial respiration and an increase in reactive oxygen species (ROS) production are not necessarily manifestations of pathology, but adaptations taking shape as the mitochondria is abdicating its adenosine triphosphate (ATP)‐producing function (which is taken over by glycolysis) and instead becomes “retooled” for an immunological role. Collectively, these observations challenge the commonly held belief that acute hyperglycemia induces mitochondrial damage leading to immune cell dysfunction. (shrink)

Several protective cellular mechanisms protect against the accumulation of reactive oxygen species (ROS) and the concomitant oxidative stress. Therefore, any reduction in glucose or fatty acid flux into cells leading to a decrease in the production of reducing equivalents would also lead to a decreased ROS production and protect cells against oxidative stress. In the presence of insulin, FOXO proteins are localized from the nucleus to the cytoplasm and degraded. An increase in cellular glucose uptake will lead (...) to increased production of ROS. This in turn activates the stress‐responsive Jun‐N‐terminal kinase (JNK), which promotes nuclear translocation of FOXO proteins, upregulating some important target genes including stress resistance. Consequently, insulin resistance should result in decreased cellular ROS production. For this reason, insulin resistance could be a physiological mechanism activated at the cellular level in response to conditions stimulating ROS production and leading to the prevention of oxidative stress, and extension of life. Concerning the whole organism, however, IR is a maladaptive process in the long term causing a diabetic state. BioEssays 29:811–818, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Ataxia‐telangiectasia (A‐T) is a pleiotropic recessive disorder characterized cerebellar ataxia, immunodeficiency, specific developmental defects, profound predisposition to cancer and acute radiosensitivity. Functional inactivation of single gene product, ATM, accounts for this compound phenotype. We suggest that ATM acts as a sensor of reactive oxygen species and/or oxidative damage cellular macromolecules, including DNA. In turn, ATM induces signalling through multiple pathways, thereby coordinating acute phase stress responses with cell cycle checkpoint control and repair of oxidative damage. Absence of (...) ATM is proposed to limit the repair of insidious oxidative damage that can occur under normal physiological conditions, ultimately leading to apoptosis of particularly sensitive cells, such as neurons and thymocytes. (shrink)

Analysis of a diverse cross‐sample of plant‐insect interactions suggests that the abundance of vitamin C (L‐ascorbic acid, ascorbate or AsA) in plants influences their susceptibility to insect feeding. These effects may be mediated by AsAs roles as an essential dietary nutrient, as an antioxidant in the insect midgut, or as a substrate for plant‐derived ascorbate oxidase, which can lead to generation of toxic reactive oxygen species. Ascorbate can also influence the efficacy of plant defenses such as myrosinases (...) and tannins, and alter insects' susceptibility to natural enemies. Conversely, herbivores appear to influence both de novo synthesis and redox cycling of AsA in their host plants, thereby potentially altering the nutritional value of crops and their susceptibility to pests. The recent development of genetically modified crops with enhanced AsA content provides both an impetus and a tool set for further studies on the role of AsA in plant‐insect interactions. (shrink)

The genetic stability of living cells is continuously threatened by the presence of endogenous reactive oxygen species and other genotoxic molecules. Of particular threat are the thousands of DNA single-strand breaks that arise in each cell, each day, both directly from disintegration of damaged sugars and indirectly from the excision repair of damaged bases. If un-repaired, single-strand breaks can be converted into double-strand breaks during DNA replication, potentially resulting in chromosomal rearrangement and genetic deletion. Consequently, cells have (...) adopted multiple pathways to ensure the rapid and efficient removal of single-strand breaks. A general feature of these pathways appears to be the extensive employment of protein–protein interactions to stimulate both the individual component steps and the overall repair reaction. Our current understanding of DNA single-strand break repair is discussed, and testable models for the architectural coordination of this important process are presented. BioEssays 23:447–455, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

No overarching hypotheses tie the basic mechanisms of mitochondrial reactive oxygen species (ROS) production to activity dependent synapse pruning—a fundamental biological process in health and disease. Neuronal activity divergently regulates mitochondrial ROS: activity decreases whereas inactivity increases their production, respectively. Placing mitochondrial ROS as innate synaptic activity sentinels informs the novel hypothesis that: (1) at an inactive synapse, increased mitochondrial ROS production initiates intrinsic apoptosis dependent pruning; and (2) at an active synapse, decreased mitochondrial ROS production masks (...) intrinsic apoptosis dependent pruning. Immature antioxidant defense may enable the developing brain to harness mitochondrial ROS to prune weak synapses. Beyond development, endogenous antioxidant defense constrains mitochondrial (ROS) to mask pruning. Unwanted age‐related synapse loss may arise when mitochondrial ROS aberrantly recapitulate developmental pruning. Placing mitochondrial ROS with their hands on the shears is beneficial in early but deleterious in later life. (shrink)

Depletion of mitochondrial endo/exonuclease G‐like (EXOG) in cultured neonatal cardiomyocytes stimulates mitochondrial oxygen consumption rate (OCR) and induces hypertrophy via reactive oxygen species (ROS). Here, we show that neurohormonal stress triggers cell death in endo/exonuclease G‐like‐depleted cells, and this is marked by a decrease in mitochondrial reserve capacity. Neurohormonal stimulation with phenylephrine (PE) did not have an additive effect on the hypertrophic response induced by endo/exonuclease G‐like depletion. Interestingly, PE‐induced atrial natriuretic peptide (ANP) gene expression was (...) completely abolished in endo/exonuclease G‐like‐depleted cells, suggesting a reverse signaling function of endo/exonuclease G‐like. Endo/exonuclease G‐like depletion initially resulted in increased mitochondrial OCR, but this declined upon PE stimulation. In particular, the reserve capacity of the mitochondrial respiratory chain and maximal respiration were the first indicators of perturbations in mitochondrial respiration, and these marked the subsequent decline in mitochondrial function. Although pathological stimulation accelerated these processes, prolonged EXOG depletion also resulted in a decline in mitochondrial function. At early stages of endo/exonuclease G‐like depletion, mitochondrial ROS production was increased, but this did not affect mitochondrial DNA (mtDNA) integrity. After prolonged depletion, ROS levels returned to control values, despite hyperpolarization of the mitochondrial membrane. The mitochondrial dysfunction finally resulted in cell death, which appears to be mainly a form of necrosis. In conclusion, endo/exonuclease G‐like plays an essential role in cardiomyocyte physiology. Loss of endo/exonuclease G‐like results in diminished adaptation to pathological stress. The decline in maximal respiration and reserve capacity is the first sign of mitochondrial dysfunction that determines subsequent cell death. (shrink)

Eukaryotic origins are heavily debated. The author as well as others have proposed that they are inextricably linked with the arrival of a pre‐mitochondrion of alphaproteobacterial‐like ancestry, in a so‐called symbiogenic scenario. The ensuing mutual adaptation of archaeal host and endosymbiont seems to have been a defining influence during the processes leading to the last eukaryotic common ancestor. An unresolved question in this scenario deals with the means by which the bacterium ends up inside. Older hypotheses revolve around the application (...) of known antagonistic interactions, the bacterium being prey or parasite. Here, in reviewing the field, the author argues that such models share flaws, hence making them less likely, and that a “pre‐symbiotic stage” would have eased ongoing metabolic integration. Based on this the author will speculate about the nature of the (endo) symbiosis that started eukaryotic evolution–in the context of bacterial entry being a relatively “early” event–and stress the differences between this uptake and subsequent ones. He will also briefly discuss how the mutual adaptation following the merger progressed and how many eukaryotic hallmarks can be understood in light of coadaptation. Also see the video abstract here https://youtu.be/ekqtNleVJpU. (shrink)