The Reactive Species Interactome: Evolutionary Emergence, Biological Significance, and Opportunities for Redox Metabolomics and Personalized Medicine

Abstract

Significance: Oxidative stress is thought to account for aberrant redox homeostasis and contribute to aging and disease. However, more often than not, administration of antioxidants is ineffective, suggesting that our current understanding of the underlying regulatory processes is incomplete.Recent Advances: Similar to reactive oxygen species and reactive nitrogen species, reactive sulfur species are now emerging as important signaling molecules, targeting regulatory cysteine redox switches in proteins, affecting gene regulation, ion transport, intermediary metabolism, and mitochondrial function. To rationalize the complexity of chemical interactions of reactive species with themselves and their targets and help define their role in systemic metabolic control, we here introduce a novel integrative concept defined as the reactive species interactome (RSI). The RSI is a primeval multilevel redox regulatory system whose architecture, together with the physicochemical characteristics of its constituents, allows efficient sensing and rapid adaptation to environmental changes and various other stressors to enhance fitness and resilience at the local and whole-organism level.Critical Issues: To better characterize the RSI-related processes that determine fluxes through specific pathways and enable integration, it is necessary to disentangle the chemical biology and activity of reactive species (including precursors and reaction products), their targets, communication systems, and effects on cellular, organ, and whole-organism bioenergetics using system-level/network analyses.Future Directions: Understanding the mechanisms through which the RSI operates will enable a better appreciation of the possibilities to modulate the entire biological system; moreover, unveiling molecular signatures that characterize specific environmental challenges or other forms of stress will provide new prevention/intervention opportunities for personalized medicine. Antioxid. Redox Signal. 27, 684–712.

Regulation of protein function by S-nitrosation and S-glutathionylation: processes and targets in cardiovascular pathophysiology

“…By now, such reactive species (ROS, RNS and RSS) are considered as players in a complex redox signaling network that interacts with protein thiol targets, acting as redox switches to control protein structure and function. Such a complex network has intriguingly been named 'reactive species interactome' (RSI), a novel concept in cell biology liable to provide critical insights for the development of prevention and treatment strategies, in what could be called today 'redox medicine' (Cortese-Krott et al, 2017). The RSI perspective is somehow complementary to (and integrated with) the redox code, and within that, to the redox proteome, another concept recently introduced to describe how protein redox-sensitive Cys residues participate in a wider network of redox switches, linked to the NAD and NADP systems and, through those, to the general metabolism of the cell (Jones and Sies, 2015).…”

“…Dysregulated S-nitrosations are usually the result of a modification of NO availability, in dependence of the specific context in which it is released, e.g. in concomitance with reactive oxygen, H 2 S and/or other reactive species (Cortese-Krott et al, 2017). In turn, NO availability results not only from alterations of the expression, compartmentation and/or activity of NOSs, but also reflects the contribution of denitrosylases, including GSNO-metabolizing enzymes such as GSNOR, producing the non-bioactive molecule GSNHOH, or GGT, producing instead reactive S-nitroso-cysteinylglycine, CGNO (Dahboul et al, 2012).…”

Heparan sulfate proteoglycan deficiency up‐regulates the intracellular production of nitric oxide in Chinese hamster ovary cell lines

“…Reactive species, from oxygen (ROS) and nitric oxide (NO), interact dynamically to maintain cell viability; allowing cells to adapt to environmental changes (Cortese‐Krott et al, ). ROS were originally associated with oxidative damage to biomolecules.…”

Hydropersulfides, the new kids in the COPD inflammatory town

“…H 2 S has accompanied life since its origin. Its toxicological potential, related to the inhibition of cellular respiration, has been known for centuries 3. Indeed, the Permian-Triassic mass extinction event has been linked to this toxicity.…”

“…Oxidative stress appears to be a (dys)functional module present in an array of chronic conditions, including hypertension, cardiovascular diseases, obesity, COPD, asthma, diabetes, neurodegenerative diseases and certain forms of cancer, that account for the majority of the global burden of disease 12. In the new paradigm for the approach to disease origin and treatment called systems medicine, oxidative stress is an important molecular hub for such set of relevant conditions,3 which we could boldly define as redox diseases 13…”