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

Abstract

Reactive oxygen species (ROS) are bioproducts of cellular metabolism. There is a range of molecules with oxidizing properties known as ROS. Despite those molecules being implied negatively in aging and numerous diseases, their key role in cellular signaling is evident. ROS control several biological processes such as inflammation, proliferation, and cell death. The redox signaling underlying these cellular events is one characteristic of the new generation of scientists aimed at defining the role of ROS in the cellular environment. The control of redox potential, which includes the balance of the sources of ROS and the antioxidant system, implies an important target for understanding the cells' fate derived from redox signaling. In this review, we summarized the chemical, the redox balance, the signaling, and the implications of ROS in biological aging.

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).

Figure 2

ROS at optimal level control cell fate by redox signaling. The balance of pro-oxidants and antioxidants maintains ROS at a safe zone for the cell. However, both the reductive (excess of antioxidant activities) and the oxidative stress can lead the cell to death. In addition, proliferation, survival, inflammation, and metabolism are some features controlled by redox signaling.

Figure 3

Cysteine oxidation is the site mainly described for redox signaling. Proteins sensitive to oxidation at thiols (cysteine amino acids contain thiols groups exposed for reaction) groups are a target for peroxide hydrogen and other oxidants. (a) First oxidation can change the conformation of the protein, which in turn will send a signal derived from this oxidation. Then, antioxidants can return the protein to its native form. However, in conditions such as oxidative stress, excessive oxidation can occur, driving proteins to irreversible inactivation, a process found in many age-related diseases. (b) Diverse oxidant can lead to a broad range of cysteine modifications that imply different signals relevant to cellular environment.

Figure 4

Crosstalk of ROS and the hallmarks of aging. The excessive production of ROS, a consequence of a redox imbalance, alters important physiological processes and increasing the susceptibility to numerous age-related diseases. Among those mechanisms include inflammation, cell death, bioenergetic failure, telomere attrition, deregulated autophagy, loss in proteostasis, proliferation, epigenetic alterations, and senescence.