Mitochondrial formation of reactive oxygen species

Abstract

The reduction of oxygen to water proceeds via one electron at a time. In the mitochondrial respiratory chain, Complex IV (cytochrome oxidase) retains all partially reduced intermediates until full reduction is achieved. Other redox centres in the electron transport chain, however, may leak electrons to oxygen, partially reducing this molecule to superoxide anion (O2-*). Even though O2-* is not a strong oxidant, it is a precursor of most other reactive oxygen species, and it also becomes involved in the propagation of oxidative chain reactions. Despite the presence of various antioxidant defences, the mitochondrion appears to be the main intracellular source of these oxidants. This review describes the main mitochondrial sources of reactive species and the antioxidant defences that evolved to prevent oxidative damage in all the mitochondrial compartments. We also discuss various physiological and pathological scenarios resulting from an increased steady state concentration of mitochondrial oxidants.

Figure 1. Sites of superoxide formation in the respiratory chain

Various respiratory complexes leak electrons to oxygen producing primarily superoxide anion (O₂⁻•). This species may reduce cytochrome c (in the intermembrane space), or may be converted to hydrogen peroxide (H₂O₂) and oxygen (in both the matrix and the intermembrane space). Increased steady state concentrations of O₂⁻• may reduce transition metals (which in turn react with H₂O₂ producing hydroxyl radicals (OH•)) or may react with nitric oxide to form peroxynitrite. Both OH• and peroxynitrite are strong oxidants which indiscriminately react with nucleic acids lipids and proteins.

Figure 2. Mechanism of electron flow in the Q-cycle in Complex III

Ubiquinone is reduced either by Complex I or II or by electrons transferred from cytochrome b on the inner side of the membrane (i), producing ubiquinol (QH₂). The reduced form transfers one electron to oxygen via the Rieske iron-sulfur protein (ISP), cytochrome c₁ and cytochrome c. The terminal oxidase is reduced by four electrons (two by copper atoms and two by cytochromes) which in turn are transferred to oxygen producing water. Cytochrome b is reduced by the ubisemiquinone formed on the outer side (Q•_(o)), but this species cannot be formed unless an electron is previously transferred by QH₂ to ISP. Superoxide may be produced on both sides of the inner membrane via the autoxidation of Q but the contribution of each pool has not yet been determined.