ROS: Basic Concepts, Sources, Cellular Signaling, and its Implications in Aging Pathways

Figure 1

Schematic overview of ROS production/elimination. NOX, located in the plasma membrane, produces O₂^{• −} in the extracellular space by transferring an electron from cytoplasmic NADPH to O₂. O₂^{• −} can be targeted by the ECSOD enzyme and converted into H₂O₂, which can permeate the plasma membrane by aquaporins or be transported to the intracellular space by ClC-3. In the cytoplasm, O₂^{• −} can be produced by XO. In addition, O₂^{• −} reacts with ^•NO to form ONOO⁻, whose decomposition results in the formation of some very reactive species, such as ^•OH, ^•NO₂, and CO₃^{• -}. However, the cytoplasmic isoform Cu/ZnSOD can act in O₂^{• −}, producing H₂O₂ targeted by MPO, forming HOCl, or by CAT, GPx, and peroxiredoxins (PRX), forming H₂O. However, through the Fenton reaction, H₂O₂ is reduced to ^•OH, a highly toxic radical in the presence of iron. In the mitochondria, electron transport chain (ETC) complexes I and III are the main sites of oxidant production, with O₂^{• −} production occurring both on the mitochondrial matrix side and in the intermembranous space of the mitochondria. Other important sources of ROS include the endoplasmic reticulum (ER), which impacts calcium signaling and proteostasis directly. Abbreviations: NADPH oxidase (NOX); chloride channel-3 (ClC-3); xanthine oxidase (XO); myeloperoxidase (MPO); endoplasmic reticulum oxidoreductin 1 (ERO1); ryanodine receptors (RyRs); sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA); oxoglutarate dehydrogenase (OGDH); pyruvate dehydrogenase complex (PDH); tumour necrosis factor α (Tnf-α); glutathione reduced (GSH); glutathione oxidized (GSSG); glutathione reductase (GR); thioredoxin (TRX); and thioredoxin reductase (TRXR).