More than Just Antioxidants: Redox-Active Components and Mechanisms Shaping Redox Signalling Network

Abstract

The concept of oxidative stress as a condition underlying a multitude of human diseases has led to immense interest in the search for antioxidant-based remedies. The simple and intuitive story of "the bad" reactive oxygen species (ROS) and "the good" antioxidants quickly (and unsurprisingly) lead to the commercial success of products tagged "beneficial to health" based solely on the presence of antioxidants. The commercial success of antioxidants by far preceded the research aimed at understanding the exact redox-related mechanisms that are in control of shaping the states of health and disease. This review describes the redox network formed by the interplay of ROS with cellular molecules and the resulting regulation of processes at the genomic and proteomic levels. Key players of this network are presented, both involved in redox signalling and control of cellular metabolism linked to most, if not all, physiological processes. In particular, this review focuses on the concept of reductive stress, which still remains less well-established compared to oxidative stress.

Keywords: antioxidants; cellular signalling; redox homeostasis; redox network; reductive stress.

Figure 1

The number of scientific articles published in the PubMed database in 1990–2019 with the term “antioxidant” and “functional food containing antioxidants” among the keywords compared to the number of products bearing information about the presence of antioxidants that were introduced to the market in 2005–2011 (on the basis of [12]).

Figure 2

The balance between oxidants and antioxidants ensures cellular redox homeostasis. The abbreviations used relate to: 6-PG—6-phosphogluconate; ADP—adenosine 5′-diphosphate; ATP—adenosine 5′-triphosphate; G6P—glucose-6-phosphate; G6PD—glucose-6-phosphate dehydrogenase; GPx—glutathione peroxidase; GR—glutathione reductase; GRX—glutaredoxin; GSH—glutathione; GSSG—GSH disulfide; H₂O₂ —hydrogen peroxide; NADPH—reduced NADP⁺; $$O_2^{• -}$$—superoxide radical; PRDX—peroxiredoxin; PSH—protein-glutathione; PSSG—protein-glutathione disulfide; SOD—superoxide dismutase; SRXN1—sulfiredoxin 1; TR—thioredoxin reductase; TRX—thioredoxin [illustration based on work of Xiao and Loscalzo [34] with modifications].

Figure 3

Oxidation of the sulfhydryl group of cysteine. Panel (A)—physiological (disulfide, sulfenic acid) and pathophysiological (sulfinic and sulfonic acid) products of cysteine oxidation. Panel (B)—the effect of disulfide bond formation on protein α-helix conformation. Panel (C)—mechanism of redox regulation on the example of the transcription factor AP-1 (activating protein 1). The enlarged view shows the DNA binding units (JunD and FosB) of AP-1. The disulfide bond between JunD and FosB (redox switch OFF) must be reduced to sulfhydryl groups to allow FosB subunit to bind to DNA (redox switch ON). Disulfide reduction is accompanied by conformational changes (dashed lines) [computer visualisation adopted from Yin et al. [78].

Figure 4

Signalling dependent on the redox status of the cell. Cellular enzymes constitutively or in response to exogenous triggers stimulate the production of ROS (red), which then affect various molecular targets (blue) modulating biological activities (yellow). The action of ROS is pleiotropic and includes the regulation of stress adaptation (including the antioxidant response), inflammatory response, cell death and metabolic adaptation (continuous arrows). A detailed description of the mechanisms is included in the text of chapter 2. The dashed arrows indicate intermediate processes. The abbreviations used refer to: AMPK—AMP-activated protein kinase; AP-1—activating protein 1; APE1/Ref-1—apurine/apyrimidine endonuclease1/redox factor 1; CAT—catalase; EGFR—epidermal growth factor receptor; ER—endoplasmic reticulum; ETC—Mitochondrial Electron Transport Chain; FOXO—transcription factor (forkhead box O); GAPDH—glyceraldehyde-3-phosphate dehydrogenase; GFR—epidermal growth factor; HIF-1—hypoxia-induced transcription factor; IκB—NF-κB inhibitor; IKK—NF-κB kinases; KEAP1—Nrf2 sensor/binding protein; MAPK—mitogen-activated kinases; mTOR—serine-threonine kinase, the so-called rapamycin mammalian target; NF-κB—nuclear factor-κB; NOX—NADPH oxidase; NRF2—nuclear factor 2; SOD1—3—superoxide dismutases; UCP—uncoupling protein.