Understanding Cellular Redox Homeostasis: A Challenge for Precision Medicine

Abstract

Living organisms use a large repertoire of anabolic and catabolic reactions to maintain their physiological body functions, many of which include oxidation and reduction of substrates. The scientific field of redox biology tries to understand how redox homeostasis is regulated and maintained and which mechanisms are derailed in diverse pathological developments of diseases, where oxidative or reductive stress is an issue. The term "oxidative stress" is defined as an imbalance between the generation of oxidants and the local antioxidative defense. Key mediators of oxidative stress are reactive species derived from oxygen, nitrogen, and sulfur that are signal factors at physiological concentrations but can damage cellular macromolecules when they accumulate. However, therapeutical targeting of oxidative stress in disease has proven more difficult than previously expected. Major reasons for this are the very delicate cellular redox systems that differ in the subcellular compartments with regard to their concentrations and depending on the physiological or pathological status of cells and organelles (i.e., circadian rhythm, cell cycle, metabolic need, disease stadium). As reactive species are used as signaling molecules, non-targeted broad-spectrum antioxidants in many cases will fail their therapeutic aim. Precision medicine is called to remedy the situation.

Keywords: antioxidants; oxidants; precision medicine; redox homeostasis.

Figure 1

Subcellular generation of reactive oxygen species and the resolving antioxidative defense. The redox potential of redox pairs as well as the concentration of ROS depend on the subcellular compartment. The concentration of H₂O₂, for instance, has been determined to be around 80 pM in the cytosol, 20 nM in the mitochondria, 700 nM in the endoplasmatic reticulum and 1–5 µM in the extracellular space (see shades of red). (Abbreviations: NOX: NADPH Oxidase; XDH: xanthine dehydrogenase; XO: xanthine oxidase; SOD: superoxide dismutase; Trx: thioredoxin, TrxR: thioredoxin reductase; GSH: glutathione; GR: glutathione reductase; GPX: glutathione peroxidase; Grx: glutaredoxin; Prdx: peroxiredoxin; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; Cav1: caveolin-1; Ero1: ER oxidoreductin 1; I3PR: inositol-3-phosphate receptor; Cyt C: cytochrome C; Casp3: caspase 3; CAT: catalase; ß-OX: ß-oxidation; LCFA: long chain fatty acid; ETC: electron transport chain; mtDNA: mitochondrial DNA; CYP: cytochrome P450; UPR: unfolded protein response; VDAC: voltage-dependent anion channel; BAK: Bcl-2-homologous antagonist killer protein).