Figure 1.

Generation of ROS and lipid peroxidation products. (A) The majority of O₂ consumed in eukaryotic cells is reduced safely to water (H₂O) by the enzyme cytochrome c oxidase in the respiratory ETC, without causing collateral damage. However, a small amount of O₂, even under normal conditions, undergoes partial reduction to produce superoxide (O₂^•−), which is usually the first ROS to be formed. O₂^•− is rapidly converted to hydrogen peroxide (H₂O₂) by superoxide dismutase (SOD), while the generated H₂O₂ is further converted to H₂O through the action of catalases (Cat), glutathione peroxidases (GPx), and peroxiredoxins (Prx). Alternatively, in the presence of available ferrous iron ions (Fe²⁺), H₂O₂ is reduced non-enzymatically by one electron, producing the highly reactive HO^•. O₂^•− and H₂O₂ are moderately reactive and can interact with a limited number of cellular macromolecules. On the contrary, HO^• is highly reactive and it can oxidize indiscriminately, with high rate constants, most, if not all molecules in living cells. (B) Lipid-derived reactive species are generated through lipid peroxidation when reactive species attack lipids and especially polyunsaturated fatty acids (PUFA). The process begins with the incorporation of O₂ and the generation of lipid hydroperoxides (ROOH). Oxidation of PUFA to ROOH can proceed either enzymatically by lipoxygenase (Lox) or non-enzymatically when a PUFA is oxidized from a free radical (X^•) to a lipid peroxyl radical (ROO^•) which subsequently attacks an adjacent PUFA. ROOH are relatively unstable and can be reduced to their corresponding innocuous alcohols (ROH) via the glutathione peroxidase 4 (GPx4). Yet, when ROOH levels elevate and Fe²⁺ is available, extremely potent alkoxyl radicals (RO^•) are generated, capable of oxidizing new PUFA, and producing damaging end-products of peroxidation. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.