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Abstract
Redox biology is at the core of life sciences, accompanied by the close correlation of redox processes with biological activities. Redox homeostasis is a prerequisite for human health, in which the physiological levels of nonradical reactive oxygen species (ROS) function as the primary second messengers to modulate physiological redox signaling by orchestrating multiple redox sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads to biomolecule damage and subsequent occurrence of various diseases such as type 2 diabetes, atherosclerosis, and cancer. Herein, starting with the evolution of redox biology, we reveal the roles of ROS as multifaceted physiological modulators to mediate redox signaling and sustain redox homeostasis. In addition, we also emphasize the detailed OS mechanisms involved in the initiation and development of several important diseases. ROS as a double-edged sword in disease progression suggest two different therapeutic strategies to treat redox-relevant diseases, in which targeting ROS sources and redox-related effectors to manipulate redox homeostasis will largely promote precision medicine. Therefore, a comprehensive understanding of the redox signaling networks under physiological and pathological conditions will facilitate the development of redox medicine and benefit patients with redox-relevant diseases.
Electron flow is one of the most fundamental and common perspectives in understanding biology.1 As Nobel prize-winning biochemist Albert Szent-Györgyi said, “Life is nothing but an electron looking for a place to rest.” Although life seems to be much more complex than electrons, the electron transfer process, which refers to the transformation of energy from an excited state (high-energy electrons) to a ground state (low-energy resting electrons) is fundamental. The rules of quantum mechanics restrain the electron transfer process whereby high-energy electrons drop spontaneously to low-energy states. Instead, they need to be offered feasible pathways, which tightly regulate the rearrangement of electrons along the energy scale. These electron transfer and transformation of energy processes make life possible.
The delivery of electrons from the donor molecules to the terminal acceptor molecules triggers oxidative (for donor molecules) and reductive (for acceptor molecules) processes, defined as redox reactions. Redox reactions are the sources of intracellular energy, harvested from electron flow during the transfer from one reductant (oxidation) to another oxidant (reduction). High-energy electrons must move to a new resting acceptor, usually molecular oxygen for aerobes, ultimately yielding H2O. For humans, intracellular enzymes reduce oxygen, which enters the cell and captures energy to accelerate ATP production. However, in some specific conditions (i.e., redox control), the reduction of oxygen is blocked at an intermediate state, such as hydrogen peroxide (H2O2), which functions as an active oxidant to modulate multiple physiological and pathological redox signaling pathways on the basis of the level of oxidants.
The delivery of electrons on the basis of energy gradients prompts the rearrangements of chemical bonds and induces cellular responses at all levels of regulation, triggering redox chemistry and redox biology simultaneously. However, how does electron flow arouse resting cells and instruct them to determine cell fate, from proliferation and differentiation to death? Many essential intermediate proteins are involved between electron flow and cellular responses, whose activities are dynamically modulated by the electron transfer process through disulfide bridges. These functional proteins act as the main executors in regulating cellular biological processes and making cell fate decisions. In the broadest sense, identifying the coordination and crosstalk between electron gradients and cellular responses is the main purpose of redox biology. Nevertheless, understanding the redox modification of these functional intermediate proteins seems to be equally important due to the close correlation of multiple diseases with aberrant redox modulation, which will largely promote the development of redox medicine. Hence, redox reactions are intimately linked to human health, in which the concept of redox homeostasis is emphasized. Constant intracellular surveillance is vital for maintaining redox homeostasis, termed “homeodynamics” due to its dynamic property.
Recent studies on redox biology have indicated a relatively complete redox architecture that is closely linked to physiological function, with a set of intricate mechanisms denoted as the “redox code.”H2O2 as a key second messenger is central to the redox code, contributing to cell fate decisions.6 In addition, the redox modifications of cysteines, such as intra- or intermolecular disulfide bond formation, S-sulfonation, S-glutathionylation, and S-nitrosylation, have also been reported to reset the function of proteins, thus, mediating the process of various cellular biological events.
Redox imbalance between oxidants and antioxidants, especially for oxidative stress (OS), accounts for many diseases including neurological disorders, immune system disorders, cardiovascular diseases, and skeletal diseases.7 Nonetheless, not all redox-related disorders are caused by excessive reactive oxygen species (ROS) production. Several pathological conditions may also result from other reactive species, such as reactive nitrogen species and reactive sulfur species, or other small signaling molecules, such as H2, NH3, and CO, which are also capable of engendering redox imbalance.
In this review, we look back at the evolution of redox biology and summarize the cellular redox landscape with a particular focus on the core redox signaling metabolite–H2O2.2, Considering the central role redox plays in determining cell fates and overall organization of living organisms, we also discuss the impacts of redox imbalance on several human diseases with an emphasis on the enormous potential of developing redox medicine. It is hoped that this systematic perspective will facilitate a better understanding of redox biology and attract more interest in the field.
Oxygen originates from the photosynthetic activity of cyanobacteria which first entered the earth's atmosphere approximately 2.3 billion years ago. The dramatic increase of O2 killed most anaerobic living creatures present at that period, with only a few aerobic life forms emerging that gradually occupied a major part in all organisms. The existence of enough O2 and its significance in producing energy for aerobes prompted the coining of the term “redox biology.”
Flohe and de Villiers et al. have reviewed several important events at the early stages of redox biology, which we have addressed and added other representative findings along this timeline (Figure 1). Generally, oxygen is highly active and can be transformed into multiple ROS, such as H2O2, singlet molecular oxygen(1O2), ozone (O3), superoxide anion radicals (O2−•), and hydroxyl radicals (OH.), by endogenous and exogenous factors. Among the major members of ROS family, H2O2 is the most frequently explored and first discovered in redox chemistry by Louis Jaques Thénard in 1818, though the underlying roles in redox biology were not defined until 1954.In 1900, catalase, which may be the first discovered antioxidant, was defined as a catalyst of H2O2.16 Intriguingly, selenium was first found and identified as a toxic chemical catalyst in 1818 and was later proven to be an essential component of the glutathione peroxidase (GPX) family.GPX was claimed to be a novel peroxidase that was independent of typical heme peroxidase in 1957, which was initially widely debated, but has gradually been accepted as GPX1 in the GPX family. In addition to the GPX family, thioredoxin reductases (TrxR), as catalysts of Trx, are well-studied selenoproteins that are classified as important oxidoreductases. Trx and peroxiredoxin (Prx) were first discovered in 1964 and 1968, respectively. They function as two essential antioxidant systems that determine cell fates and pathophysiological changes in response to various stresses.
Intracellular H2O2 is endogenously derived from NADPH oxidase (NOX), mitochondrial oxidative phosphorylation (mtOXPHOS ) (i.e., the electron transport chain [ETC] of mitochondria), and other cell compartments, including peroxisomes and the endoplasmic reticulum (ER), or exogenously arises from stress such as ultraviolet radiation, ionizing radiation, and toxic compounds. Early in 1961, Iyer et al. found that H2O2 was released from phagocytosis of guinea pig polymorphonuclear leukocytes. Later, in 1964, Rossi and colleagues confirmed that NOX was the upstream event in H2O2 production, answering how phagocytes generated H2O2 by respiratory burst. However, NOX was first disclosed to generate superoxide radicals and H2O2 by Sbarra and Karnowski in 1959. In 1973, a study by Babior et al. confirmed that in the process of respiratory burst, O2−• but not H2O2 was the direct product, meaning that H2O2 originated from O2−• during metabolic activity. In fact, before this finding, in 1969 McCord and Fridovich reported that O2−• can be converted into two new forms–oxygen and H2O2 by bovine erythrocyte-derived superoxide dismutase (SOD) . ETC of mitochondria was first proven to be the source of H2O2 in 1967, and in 1974, Loschen et al. similarly elucidated that O2−• was also the precursor of H2O2 in mitochondria.
For a long time, ROS were identified as toxic byproducts of redox reactions, damaging biomacromolecules (e.g., DNA,RNA, proteins, and lipids) and causing cell death or malignant transformation. In 1954 and 1956, Gershman and Harman described that oxidant burden was closely correlated with tissue injury and aging, which greatly promoted the theory of ROS as poisonous byproducts.43, 44 However, when in-depth studies were carried out, the roles of ROS in not only damaging but also regulating physiological signaling pathways depending on ROS levels were defined.Thus, for H2O2, under the tight control of cellular physiological signaling and antioxidant systems, the concentration of intracellular H2O2 is maintained at a physiological level (ranging from 1–100 nM) and modulates cell proliferation, differentiation and death, whereas a supraphysiological H2O2 level (above 100 nM) destroys biomacromolecules that control cell fates. In between these levels, there is a small window of the adjustable interval, where intracellular adaptive antioxidant systems are activated through Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (Nrf2/Keap1) and nuclear factor kappa B (NF-κB), which partially reverse the detrimental impacts. Nrf2, which can induce the expression of phase II detoxifying enzyme genes through antioxidant response elements (AREs), was defined as a master regulator of antioxidant systems in 1997.A typical example of ROS acting as an essential physiological signaling agent is reflected in immune defense,13 in which intracellular H2O2 triggers the migration of leukocytes to lesions through several possible mechanisms.
In summary, research in the last century has found multiple pivotal redox regulators and disclosed their roles in redox modulation. In addition, the main sources of ROS were also partially illustrated. Additionally, ROS was found to have more functions including physiological and pathological significance. Currently, the role of redox biology is continually being extended. For instance, researchers have found more NOX subunits in recent years.
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Jing Zuo, Zhe Zhang, and Maochao Luo
James Eckburg
