Fig. 1. Simplified schematic of A) sources of ROS and B) ROS detoxification by the antioxidant defense system.

Sources of ROS generation in the cardiomyocyte including mitochondrial electron transport chain (ETC), monoamine oxidases (MAO), calpains, nicotinamide adenine dinucleotide (NADH) oxidases (NOX), xanthine oxidase (XO) and uncoupled nitric oxide synthase (NOS). Complex I (NADH dehydrogenase) transfers electrons from NADH and passes to ubiquinone (Q). Complex II (succinate dehydrogenase; SDH) donates electrons from succinate (as part of the Krebs cycle) to Q via FeS clusters. Complex III (cytochrome c oxidoreductase) transfers the electrons carried by ubiquinol (QH2) to cytochrome c (Cyt c). Complex IV (cytochrome c oxidase) transfers electrons (e−) from cytochrome c to O2 to generate water (H2O). Complex V (F1F0 ATP synthase) exchanges protons from the IMS to the matrix, which drives phosphorylation of ADP to form ATP. MAO generates H₂O₂ and reactive aldehydes as by-products during the oxidation of monoamines. NOX forms a heterodimer with p22^phox and produces ${\text{O}}_2^{•-}$ upon electron transfer from NADPH to molecular O₂. XO reacts with molecular oxygen to produce ${\text{O}}_2^{-}$ and H₂O₂ during the production of uric acid. NOS consumes NADPH and O₂ to convert L-arginine to L-citrulline, generating NO and NADP as by-products. I–V: Denotes ETC complex number. B) Generation of ROS is counterbalanced by the antioxidant defense system. Superoxide is converted to hydrogen peroxide (H₂O₂) by superoxide dismutase (SOD). H₂O₂ is converted to H₂O by glutathione peroxidase (GSH-Px), peroxiredoxin (PRX) or catalase (CAT). Activity of PRX is regulated by sulfiredoxin (SRX) and thioredoxin (TRX), which is further regulated by TRX reductase (TRXR) and its endogenous inhibitor, thioredoxin interacting protein (TXNIP). Blue indicates active state. Orange indicates inactive state. Intermembrane space (IMS). Proteins have been compartmentalized according to their predominant intracellular localization.