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. 2013 Feb 1;18(4):432–468. doi: 10.1089/ars.2011.4234

FIG. 2.

FIG. 2.

Major ROS synthesis pathways in cardiac myocytes. In the mitochondria (MITO), a small percentage of electrons from the respiratory chain prematurely leak to O2 at complexes I, II, or III, resulting in the formation of the toxic superoxide radical ion (O2•−). O2•− is also generated by release of a free electron from the reactions where NADPH is oxidized to NADP by NADPH oxidase, and hypoxanthine is oxidized to xanthine (X) by xanthine oxidase (XO). The O2•− generated in the mitochondria can freely pass through the mitochondrial membrane into the cytosol. Cytosolic O2•− can interact with other intracellular molecules to generate (hydroxyl radical [OH•], a neutral form of the OH) from H2O2. This H2O2, but not O2•−, is mainly generated in the peroxisomes of the cells. When peroxisomes are damaged, their H2O2-consuming enzymes are downregulated, and H2O2 releases into the cytosol (62). In a Haber–Wiess reaction, O2•− reacts with H2O2 to form OH• and a hydroxyl anion (OH−). Moreover, under conditions of metabolic stress, iron-containing molecules in a cell, such as 4Fe-4S cluster-containing enzymes, release free iron. This iron participates in a Fenton reaction generating OH• radical. The Haber–Wiess and the Fenton reactions occur in conjunction, because the OH− released from the Haber–Wiess reaction feeds into the Fenton reaction to form more OH•. The reduction of Fe by O2•− yielding Fe2+ and O2 further propels the Fenton reaction. Other radicals derived from O2 that can be formed in living systems are lipid peroxyl radicals (RCOO•) that are synthesized due to peroxidation of the membrane lipids (6). Overproduction of nitrogen species is called nitrosative stress. Reactive nitrogen species (RNS) are formed from a single nitrogen radical (NO•) generated in cells by nitric oxide synthase (NOS), which metabolizes l-arginine (l-Arg) to l-citruline (l-Cit) with the formation of NO• (145). NO• and O2•− react together to produce a much more potent oxidative molecule peroxynitrite anion (ONOO−). The figure was created by adapting information from (176, 195, 255), respectively.