Bioelectronome. Integrated approach to receptor chemistry, radicals, electrochemistry, cell signaling, and physiological effects based on electron transfer

Bioelectronome refers to the host of electron transfer (ET) reactions that occur in living systems. This review presents an integrated approach to receptor chemistry based on electron transfer, radicals, electrochemistry, cell signaling, and end result. First, receptor activity is addressed from the unifying standpoint of redox transformations in which various receptors are discussed. After a listing of receptor-binding modes, receptor chemistry is treated with focus on generation of reactive oxygen species (ROS), activation by ROS, and subsequent cell signaling involving ROS. A general electrostatic mechanism is proposed for receptor-ligand action with supporting evidence. Cell-signaling processes appear to entail electron transfer, ROS, redox chains, and relays. The widespread involvement of phosphate from phosphorylation may be rationalized electrostatically by analogy with DNA phosphate. Extensive evidence supports important participation of ET functionalities in the mechanism of drugs and toxins. The integrated approach is applied to the main ET classes, namely, quinones, metal complexes, iminium species, and aromatic nitro compounds.     

Bioelectronome. Integrated Approach to Receptor Chemistry,Radicals, Electrochemistry,Cell Signaling,and Physiological Effects Based on Electron Transfer

Bioelectronome refers to the host of electron transfer (ET) reactions that occur in living systems. This review presents an integrated approach to receptor chemistry based on electron transfer, radicals, electrochemistry, cell signaling, and end result. First, receptor activity is addressed from the unifying standpoint of redox transformations in which various receptors are discussed. After a listing of receptor-binding modes, receptor chemistry is treated with focus on generation of reactive oxygen species (ROS), activation by ROS, and subsequent cell signaling involving ROS. A general electrostatic mechanism is proposed for receptor-ligand action with supporting evidence. Cell-signaling processes appear to entail electron transfer, ROS, redox chains, and relays. The widespread involvement of phosphate from phosphorylation may be rationalized electrostatically by analogy with DNA phosphate. Extensive evidence supports important participation of ET functionalities in the mechanism of drugs and toxins. The integrated approach is applied to the main ET classes, namely, quinones, metal complexes, iminium species, and aromatic nitro compounds.     

Reactive oxygen species generation and signaling in plants

The introduction of molecular oxygen into the atmosphere was accompanied by the generation of reactive oxygen species (ROS) as side products of many biochemical reactions. ROS are permanently generated in plastids, peroxisomes, mitochiondria, the cytosol and the apoplast. Imbalance between ROS generation and safe detoxification generates oxidative stress and the accumulating ROS are harmful for the plants. On the other hand, specific ROS function as signaling molecules and activate signal transduction processes in response to various stresses. Here, we summarize the generation of ROS in the different cellular compartments and the signaling processes which are induced by ROS.Keyword: reactive oxygen species, signal transduction, plastids     

Microbial energetics and stoichiometry for biodegradation of aromatic compounds involving oxygenation reactions

Oxygenation reactions significantly alter the energy and electron flows and, consequently, the overall stoichiometry for the microbial utilization of aromatic compounds. Oxygenation reactions do not yield a net release of electrons, but require an input of electrons to reduce oxygen molecules. The biodegradation pathway of phenanthrene as a model compound was analyzed to determine the impact of oxygenation reactions on overall stoichiometry using the half-reaction method. For individual oxygenation reactions, the half-reaction method for analyzing the electron and energy flows must be modified, because the reactions do not release electrons for synthesis or energy generation. Coupling the oxygenation reaction to subsequent reaction steps provides a net electron release for the coupled reactions. Modeling results indicate that oxygenation reactions increase the oxygen requirement and reduce the cell yield, compared to the conventional mineralization represented by hydroxylation reactions in place of oxygenations. The computed yields considering oxygenation reactions conform better to empirical yields reported in the literature than do yields computed by the hydroxylation single-step methods. The coupled-reaction model also is consistent with information about the ways in which micro-organisms that degrade aromatics accumulate intermediates, regulate degradation genes, and organize enzyme clusters.     

Biophoton research in blood reveals its holistic properties

Monitoring of spontaneous and luminophore amplified photon emission (PE) from non-diluted human blood under resting conditions and artificially induced immune reaction revealed that blood is a continuous source of biophotons indicating that it persists in electronically excited state. This state is pumped through generation of electron excitation produced in reactive oxygen species (ROS) reactions. Excited state of blood and of neutrophil suspensions (primary sources of ROS in blood) is an oscillatory one suggesting of interaction between individual sources of electron excitation. Excited state of blood is extremely sensitive to the tiniest fluctuations of external photonic fields but resistant to temperature variations as reflected in hysteresis of PE in response to temperature variations. These data suggest that blood is a highly cooperative non-equilibrium and non-linear system, whose components unceasingly interact in time and space. At least in part this property is provided by the ability of blood to store energy of electron excitation that is produced in course of its own normal metabolism. From a practical point of view analysis of these qualities of blood may be a basement of new approach to diagnostic procedures.     

Iron homeostasis and oxidative stress: An intimate relationship

Iron is a transition metal and essential constituent of almost all living cells and organisms. As component of various metalloproteins it is involved in critical biochemical processes such as transport of oxygen in tissues, electron transfer reactions during respiration in mitochondria, synthesis and repair of DNA, metabolism of xenobiotics, etc. However, when present in excess within cells and tissues, iron disrupts redox homeostasis and catalyzes the propagation of reactive oxygen species (ROS), leading to oxidative stress. ROS are critical for physiological signaling pathways, but oxidative stress is associated with tissue injury and disease. At the cellular level, oxidative stress may lead to ferroptosis, an iron-dependent form of cell death. In this review, we focus on the intimate relationship between iron metabolism and oxidative stress in health and disease. We discuss aspects of redox- and iron-mediated signaling, toxicity, ferroptotic cell death, homeostatic pathways and pathophysiological implications.     

Role of Reactive Oxygen Species in the Initiation of Plant Retrograde Signaling

The interaction between the nucleus and the different organelles is important in the physiology of the plant. Reactive oxygen species (ROS) are a by-product of the oxidation of organic molecules to obtain energy by the need to carry out the electron transfer between the different enzymatic complexes. However, they also have a role in the generation of what is known as retrograde signaling. This signal comes from the different organelles in which the oxidation of molecules or the electron transference is taking place such as mitochondria and chloroplasts. Furthermore, ROS can also induce the release of signals from the apoplast. It seems that these signals plays a role communicating to the nucleus the current status of the different parts of the plant cell to induce a changes in gene expression. In this review, the molecular mechanism of ROS retrograde signaling is described.

     

Molecular mechanisms of cellular injury produced by neurotoxic amino acids that generate reactive oxygen species

Summary There is now strong experimental evidence that the basic precursors for the synthesis of catechol(amine) and indolamine neurotransmitters, tyrosine and tryptophan can act as generators of ROS (reactive oxygen species): peroxides, superoxide and peroxyradicals. The consequences of free radicals formation from precursors during oxidative degradation process, their possible participation in electron transfer/addition reactions and chain processes involving cell antioxidant defense system were presented and discussed. Although the generation of neurotoxic ROS by tyrosine and tryptophan is accepted to occur in the presented model systems, doubts can exist as to the situationin vivo, which may be completely different and remain to be explored. The relevance of the present findings with regard to a variety of neurological diseases cannot be ignored.     

Integrated approach to the mechanisms of thyroid toxins: electron transfer,reactive oxygen species,oxidative stress,cell signaling,receptors, and antioxidants

Although considerable numbers of reviews are available on toxicity of major body organs based on electron transfer (ET), reactive oxygen species (ROS), and oxidative stress (OS), the integrated concept has been less applied to glands. This review represents an interdisciplinary approach to thyroid toxicity, involving ET, ROS, OS, cell signaling, receptors, toxicants, and beneficial effects of antioxidants (AOs). The introductory portion includes general function of the thyroid as well as the mechanism of thyroxine synthesis entailing participation of oxidative events, including the role of iodine. Various ROS, both endogenous and exogenous, are importantly involved in the diverse toxic manifestations. Discussion is centered on hydrogen peroxide and lipid peroxides. There is also treatment of receptor-ligand activity. Cell signaling participates in the various biochemical events taking place in the thyroid, both beneficial and adverse. In addition, the mechanism of cell signaling is discussed based on radicals, ET, relays, conduits, and electrochemistry. In addition to endogenous toxins, various exogenous ones are addressed, falling in diverse classes. Data indicate involvement of ET-ROS-OS in the toxic manifestations. Large numbers of reports reveal the beneficial effects of AOs in countering the toxicity, which is in accord with the mechanistic framework.     

A comparison of arteries and veins in oxidative stress: producers, destroyers, function, and disease

Reactive oxygen species (ROS) are by-products of oxygen metabolism, normally present in low levels inside cells, where they participate in signaling processes. The delicate balance in the continuous cycle of ROS generation and inactivation is maintained by enzymatic and nonenzymatic endogenous systems. Overwhelming production of ROS (by such sources as the mitochondrial electron transport chain, NADPH oxidase, xanthine oxidase, or uncoupled nitric oxide synthase), when inadequately counteracted by destruction through antioxidant systems (such as superoxide dismutase or catalase), leads to a prooxidant state also known as oxidative stress. Increased levels of ROS and markers of oxidative stress have been consistently found in such cardiovascular diseases as atherosclerosis or hypertension, although controversy still exists over the pathophysiological role of oxidative stress in these conditions. ROS can modulate vascular function either by direct oxidative damage or by activating cellular signaling pathways that lead to abnormal contractile, inflammatory, proliferative, or remodeling properties of the blood vessel. Most current research focuses on these processes in arteries, leaving veins, "the other side" of vascular biology, in obscurity. Veins are different structurally and functionally from arteries. Equipped with a smaller smooth muscle layer compared to arteries, but being able to accommodate 70% of the circulating blood volume, veins can modulate cardiovascular homeostasis and contribute significantly to hypertension pathogenesis. Although the reports on the quantitative differences in ROS production in veins compared to arteries had conflicting results, there is a clear qualitative difference in ROS metabolism and utilization between the two vessel types. This review will compare and contrast the current knowledge of ROS metabolism in arteries versus veins in both physiological and pathophysiological conditions. Our understanding of the mechanisms underlying vascular diseases would greatly benefit from a more thorough exploration of the role of veins and venous oxidative stress.     

Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature

In the pulmonary vasculature, the mechanisms responsible for oxygen sensing and the initiation of hypoxia-induced vasoconstriction and vascular remodeling are still unclear. Nitric oxide (NO) and reactive oxygen species (ROS) are discussed as early mediators of the hypoxic response. Here, we describe a quantitative analysis of NO- and ROS-producing cells within the vascular walls of murine lung sections cultured at normoxia or hypoxia. Whereas the number of NO-producing cells was not changed by hypoxia, the number of ROS-generating cells was significantly increased. Addition of specific inhibitors revealed that mitochondria were the source of ROS. The participation of the individual mitochondrial complexes differed in normoxic and hypoxic ROS generation. Whereas normoxic ROS production required complexes I and III, hypoxic ROS generation additionally demanded complex II. Histochemically demonstrable succinate dehydrogenase activity of complex II in the arterial wall decreased during hypoxia. Inhibition of the reversed enzymatic reaction, i.e., fumarate reductase, by application of succinate, specifically abolished hypoxic, but not normoxic, ROS generation. Thus complex II plays an essential role in hypoxic ROS production. Presumably, its catalytic activity switches from succinate dehydrogenase to fumarate reductase at reduced oxygen tension, thereby modulating the directionality of the electron flow.     

Reactive oxygen species production by forward and reverse electron fluxes in the mitochondrial respiratory chain

Reactive oxygen species (ROS) produced in the mitochondrial respiratory chain (RC) are primary signals that modulate cellular adaptation to environment, and are also destructive factors that damage cells under the conditions of hypoxia/reoxygenation relevant for various systemic diseases or transplantation. The important role of ROS in cell survival requires detailed investigation of mechanism and determinants of ROS production. To perform such an investigation we extended our rule-based model of complex III in order to account for electron transport in the whole RC coupled to proton translocation, transmembrane electrochemical potential generation, TCA cycle reactions, and substrate transport to mitochondria. It fits respiratory electron fluxes measured in rat brain mitochondria fueled by succinate or pyruvate and malate, and the dynamics of NAD(+) reduction by reverse electron transport from succinate through complex I. The fitting of measured characteristics gave an insight into the mechanism of underlying processes governing the formation of free radicals that can transfer an unpaired electron to oxygen-producing superoxide and thus can initiate the generation of ROS. Our analysis revealed an association of ROS production with levels of specific radicals of individual electron transporters and their combinations in species of complexes I and III. It was found that the phenomenon of bistability, revealed previously as a property of complex III, remains valid for the whole RC. The conditions for switching to a state with a high content of free radicals in complex III were predicted based on theoretical analysis and were confirmed experimentally. These findings provide a new insight into the mechanisms of ROS production in RC.     

Mitochondrial metabolism of reactive oxygen species

For a long time mitochondria have mainly been considered for their role in the aerobic energy production in eukaryotic cells, being the sites of the oxidative phosphorylation, which couples the electron transfer from respiratory substrates to oxygen with the ATP synthesis. Subsequently, it was showed that electron transfer along mitochondrial respiratory chain also leads to the formation of radicals and other reactive oxygen species, commonly indicated as ROS. The finding that such species are able to damage cellular components, suggested mitochondrial involvement in degenerative processes underlying several diseases and aging.More recently, a new role for mitochondria, as a system able to supply protection against cellular oxidative damage, is emerging. Experimental evidence indicates that the systems, evolved to protect mitochondria against endogenously produced ROS, can also scavenge ROS produced by other cellular sources. It is possible that this action, particularly relevant in physio-pathological conditions leading to increased cellular ROS production, is more effective in tissues provided with abundant mitochondrial population. Moreover, the mitochondrial dysfunction, resulting from ROS-induced inactivation of important mitochondrial components, can be attenuated by the cell purification from old ROS-overproducing mitochondria, which are characterized by high susceptibility to oxidative damage. Such an elimination is likely due to two sequential processes, named mitoptosis and mitophagy, which are usually believed to be induced by enhanced mitochondrial ROS generation. However, they could also be elicited by great amounts of ROS produced by other cellular sources and diffusing into mitochondria, leading to the elimination of the old dysfunctional mitochondrial subpopulation.     

Cell signaling (mechanism and reproductive toxicity): redox chains, radicals, electrons, relays, conduit, electrochemistry, and other medical implications

This article deals with a novel, simple, integrated approach to cell signaling involving basic biochemical principles, and their relationship to reproductive toxicity. Initially, an overview of the biological aspects is presented. According to the hypothetical approach, cell signaling entails interaction of redox chains, involving initiation, propagation, and termination. The messengers are mainly radicals and electrons that are generated during electron transfer (ET) and hydrogen atom abstraction reactions. Termination and initiation processes in the chain occur at relay sites occupied by redox functionalities, including quinones, metal complexes, and imines, as well as redox amino acids. Conduits for the messengers, comprising species with nonbonding electrons, are omnipresent. Details are provided for the various electron transfer processes. In relation to the varying rates of cell communication, rationale is based on electrons and size of radicals. Another fit is similarly seen in inspection of endogenous precursors of reactive oxygen species (ROS); namely, proteins bearing redox moieties, lipid oxidation products, and carbohydrate radicals. A hypothesis is advanced in which electromagnetic fields associated with mobile radicals and electrons play a role. Although radicals have previously been investigated as messengers, the area occupies a minor part of the research, and it has not attracted broad consensus as an important component. For the first time, an integrated framework is presented composed of radicals, electrons, relays, conduits, and electrical fields. The approach is in keeping with the vast majority of experimental observations. Cell signaling also plays an important role in reproductive toxicity. The main classes that cause birth defects, including ROS, radiation, metal compounds, medicinals, abused drugs, and miscellaneous substances, are known to participate in the signaling process. A unifying basis exists, in that both signaling and reproductive toxicity are characterized by the electron transfer-reactive oxygen species-oxidative stress (ET-ROS-OS) scheme. This article also incorporates representative examples of the extensive investigations dealing with various medical implications. There is considerable literature pointing to a role for cell communication in a wide variety of illnesses.     

T cell receptor stimulation, reactive oxygen species, and cell signaling

In the immune system, much of the focus on reactive oxygen species (ROS) has been regarding their role in antimicrobial defense as part of the innate immune system. In addition to this role, it is now becoming clear that ROS are used by cells of the adaptive immune system as regulators of signal transduction by cell surface receptors. The activation of T lymphocytes through their specific antigen receptor [T cell receptor (TCR)] is vital in regulating the immune response. Much experimental evidence has suggested that activation of T cells is redox dependent and recent studies have shown that engagement of the TCR induces rapid production of ROS. This review examines the evidence for TCR-stimulated generation of ROS and discusses the role(s) of receptor-stimulated ROS production in T cell signal transduction and gene expression.     

Interaction of molecular oxygen with the donor side of photosystem II after destruction of the water-oxidizing complex

Photosystem II (PSII) is a pigment-protein complex of thylakoid membrane of higher plants, algae, and cyanobacteria where light energy is used for oxidation of water and reduction of plastoquinone. Light-dependent reactions (generation of excited states of pigments, electron transfer, water oxidation) taking place in PSII can lead to the formation of reactive oxygen species. In this review attention is focused on the problem of interaction of molecular oxygen with the donor site of PSII, where after the removal of manganese from the water-oxidizing complex illumination induces formation of long-lived states (P680^+· and TyrZ^·) capable of oxidizing surrounding organic molecules to form radicals.     

The mitochondrial compartment

Mitochondria are vital organelles that perform a variety of fundamental functions ranging from the synthesis of ATP through to being intimately involved in programmed cell death. Comprised of at least six compartments: outer membrane, inner boundary membrane, intermembrane space, cristal membranes, intracristal space, and matrix, mitochondria have a complex, dynamic internal structure. This internal dynamism is reflected in the pleomorphy and motility of mitochondria. Mitochondria contain their own DNA (mtDNA), encoding a small number of vital genes, but this role as a genetic vault is not compatible with the role of mitochondria in bioenergetics since electron transport results in the generation of reactive oxygen species (ROS) that induce lesions in the mtDNA. It is hypothesized that ROS shape the morphological organization of the higher plant cell mitochondrial population into a discontinuous whole, and that ROS are a selective pressure affecting the organization of the mitochondrial genome. This review describes how inter- and intra-mitochondrial compartmentalization underpins the biology of this complex organelle.     

The mitochondrial compartment

Mitochondria are vital organelles that perform a variety of fundamental functions ranging from the synthesis of ATP through to being intimately involved in programmed cell death. Comprised of at least six compartments: outer membrane, inner boundary membrane, intermembrane space, cristal membranes, intracristal space, and matrix, mitochondria have a complex, dynamic internal structure. This internal dynamism is reflected in the pleomorphy and motility of mitochondria. Mitochondria contain their own DNA (mtDNA), encoding a small number of vital genes, but this role as a genetic vault is not compatible with the role of mitochondria in bioenergetics since electron transport results in the generation of reactive oxygen species (ROS) that induce lesions in the mtDNA. It is hypothesized that ROS shape the morphological organization of the higher plant cell mitochondrial population into a discontinuous whole, and that ROS are a selective pressure affecting the organization of the mitochondrial genome. This review describes how inter- and intra-mitochondrial compartmentalization underpins the biology of this complex organelle.     

Lipid radicals--possible mediators of charge transfer and energy transformation (a hypothesis)

A number of enzymatic reactions with the participation of lipid radicals is discussed in the article. It is supposed that NADPH- and NADH-dependent formation of the lipid radicals has a functional importance. The uptake of oxygen by free radicals is considered as one of the reactions of radicals utilization. It is proposed that other reactions with participation of lipid radicals can take place in the membranes of microsomes and mitochondria: the reaction of electron transfer from flavoprotein to cytochrome P448 and the reaction of energy transfer which provide the coupling of oxidation and phosphorylation.     

线粒体，活性氧和细胞凋亡

在能量代谢和自由基代谢中,线粒体均占据着十分重要的地位.通过呼吸链电子漏途径,线粒体产生大量超氧阴离子,并通过链式反应形成对机体有损伤作用的活性氧.通过呼吸链电子漏,氧化磷酸化解偶联,线粒体内膜产生通透性转变孔道（PTP）及Box-和/或PTP-介导的细胞色素c向胞质的转移等种种因素,线粒体参与一般抗氧化防御及细胞凋亡等重要生理过程的调控.在与线粒体相关的细胞凋亡中,活性氧的信号作用是十分明显的.