The Role of Redox Signaling in Enhancing Cellular Function

Oxidation of proteins at cysteine residues is a significant signaling tool in living systems. Oxidation can either modify the conformation of a protein or inhibit its function by changing its active site.

Redox signals are used to regulate proliferation, cell survival, and inflammation. They also control metabolic reprogramming, macrophage and T helper cell polarization, anti-viral and antibacterial responses, and aging.

ASEA Redox is a liquid supplement marketed as a source of "redox signaling molecules" that are claimed to support cellular health and overall well-being. Many different genes are regulated by transcription factors, which act as the "controllers" of gene expression.

They bind to specific regions of DNA called enhancers, which are located next to a regulated gene. This is known as the "smart regulation" of genes; they are expressed when and how much they need to be, according to environmental conditions.

Filamentous fungi have developed intricate signal transduction pathways to detect and respond to oxidative stress in various forms. This response involves the modulation of transcription of the antioxidant genes to protect against oxidative damage.

The redox-sensitive transcription factor Nrf2 (Nrf2o, NFE2L2) is a well-known example. It binds to the cis-elements known as the antioxidant response elements (ARE) or electrophile-responsive elements in promoter sequences of genes that encode antioxidant enzymes.

Exposure to oxidative stress induces the expression of Nrf2, which binds to Keap1, activating it and increasing the expression of these phase II detoxifying enzymes. Activation of NF-kB and HIF-1 also occurs as a result of oxidative stress.

The thiol-containing domains of these redox-sensitive transcription factors are targets for chemoprevention and chemoprotection by various anti-inflammatory and antioxidant phytochemicals.

The oxidation state of proteins is a critical control point in many redox-sensing pathways. Depending on their redox state, proteins may become activated or inactivated.

Redox-sensitive proteins are characterized by the presence of one or more cysteines. Reactive oxygen species readily modify these redox-sensitive cysteines to induce functional changes in the protein.

The oxidative modification is rapidly reversed by dedicated redox balancing systems, such as the glutaredoxin and thioredoxin systems that draw their reducing power from NADPH.

These redox-sensitive proteins are also often modified by reactive metabolites. In the case of protein phosphatases, this results in phosphorylation at the redox-sensitive Cys residue.

For example, shikonin, a natural naphthoquinone derivative, triggers apoptosis by inducing the activation of ASK1 and JNK. In addition, the apoptosis signaling kinase (ASK1) phosphorylated the redox-sensitive protein PERK.

It leads to a decrease in cellular ATP and an increase in ROS production. In addition, the redox-sensitive proteins RLA0 and RLA1 are phosphorylated by ASK1. These modifications result in the apoptosis of cells through the mitochondrial apoptotic pathway.

Redox-sensitive proteins, such as thioredoxins/thioredoxin reductases (Trx/TrxR) and peroxiredoxins (Prxs), maintain cellular redox homeostasis. However, excessive oxidative stress levels lead to their accumulation, triggering redox signaling events such as autophagy, apoptosis, and necrosis.

The cysteine residues in these redox-sensitive proteins are partially ionized at physiological pH. They are susceptible to H2O2 oxidation, which results in the formation of sulfenic acid or its salt (2). This sulfenylation can be intra- or intermolecular and can involve disulfide bonds with glycine or glutathione, respectively.

Using hydrogen/deuterium exchange mass spectrometry (HDX-MS), we showed that mild oxidation of Prx2 caused conformational changes that exposed its C-terminal residue Lys191 to the solvent. It enables the protein to be ubiquitinated by a redox-sensitive ligase, RND1 (Fig. 1a), and degraded by proteasomes or autophagy.

Moreover, HDX-MS revealed that the pI of the oxidized Prx2 shifts to an acidic region on 2D gels during recovery after treatment with 0.5 mM H2O2. These findings suggest that structural changes of redox-sensitive proteins and their degradation play essential roles in H2O2 homeostasis.

The availability of molecular oxygen (O2) is a critical environmental cue for regulating cellular function in aerobic organisms. It controls the synthesis of adenosine triphosphate (ATP), a significant energy source in cells.

O2 sensing by a group of cation-permeable channels formed by TRPA proteins has emerged as an essential mechanism in the immediate acute physiological responses to changes in oxygen availability.

Cellular redox signaling via ROS has been shown to modulate autophagy by upregulating the phosphatases JNK and p38, activating the apoptosis-inducing pathway through the kinases MAPK - and p53 [45]. The persistent activation of JNK and p38 may also result in oxidative damage to DNA and lead to cell death.

The redox-sensitive protein, TIGAR, is known to interact with and control a series of enzymes involved in maintaining the redox balance, including thioredoxin (Trx), and selenoproteins such as Asp/Glu/Ser/Phe and apoptosis signal-regulating kinase 1 (ASK1).