# Arsenic: A Review on a Great Health Issue Worldwide
## 6 Effects of Arsenic in Mitochondrial Dysfunction  
Mitochondria are cellular organelles responsible for the oxidation-reduction reaction of the food of our diet for the production of ATP, owing to the electron transport chain and oxidative phosphorylation. The mitochondrial reactions take place in the presence of oxygen with the production of free radicals and oxidative stress. Under physiological conditions, normal levels of reactive oxygen species (ROS) are maintained by enzymatic and non-enzymatic antioxidant mechanisms, whereas in conditions of damaged or aged mitochondria, ROS formation increases [57]. The exposure to the xenobiotic arsenic causes disruption of mitochondrial function, inhibition of mitochondrial utilization, leading to disturbed membrane potential, and decreased ATP levels. Arsenic inhibits mitochondrial complex I (NADH ubiquinone oxidoreductase), complex II (succinate dehydrogenase), and complex IV (cytochrome c oxidase), followed by increased ROS production, lipid peroxidation, protein, and DNA damage [58]. During arsenic poisoning, glycolysis produces pyruvate without net ATP production, as arsenate ions compete with phosphate ions due to their structural similarities. Normally, the enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) oxidizes, in the presence of inorganic phosphate, glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, that in turn is converted to 3-phosphoglycerate in the presence of phosphoglycerate kinase, releasing one molecule of ATP. It must be pointed out that this enzyme can also catalyze the reaction between arsenate and glyceraldehyde-3-phosphate to form 1-arseno-3-phosphoglycerate that hydrolyzes to arsenate and 3-phosphoglycerate without forming any ATP molecule. Arsenate actually competes with the inorganic phosphate for the GAPDH. This event happens cyclically. In fact, released arsenate reacts again to glyceraldehyde-3-phosphate resulting in the loss of ATP production. Therefore, at mitochondrial level, arsenate uncouples the oxidative phosphorylation. In the presence of arsenate in lieu of ATP, ADP-arsenate is produced. ADP-arsenate is not stable as ATP and hydrolyzes causing depletion of ATP. Arsenic inhibits also two important metabolic enzymatic complexes. The first complex is pyruvate dehydrogenase (glycolytic pathway) (Figure 2), and the second one is ketoglutate dehydrogenase (Krebs tricarboxylic acids cycle). The enzymes and the co-enzymes of oxidative decarboxylation of pyruvate and ketoglutate are the same, concerning the reactions mechanism: pyruvate/ketoglutate decarboxylase, dihydropliogly transacetylase/dihydropli transsuccinylase, dihydropliogly dehydrogenase, thiamine pyrophosphate (TPP), lipoic acid, CoASH (Co-enzyme A), FAD, and NAD\({}^{+}\). Arsenic affects the conversion of lipoic acid to acetyl-CoA and succinyl-CoA interfering with -SH groups of reduced dihydropliophage. Arsenic forms a covalent adduct with dihydropliopic acid inhibiting the regeneration of lipoic acid. Arsenic halts the formation of acetyl-CoA and succinyl-CoA, as well as the TCA cycle and ultimately respiration is ceased without ATP synthesis. Ketoglutate dehydrogenase complex closely resembles the pyruvate dehydrogenase complex in both structure, function, and mechanism.