Fig. 1.

Schematic diagram of electron and proton flow along the respiratory chain complexes (CI-CIV) of the inner mitochondrial membrane. Electrons (dotted line) from NADH (CI) and FADH₂ (CII) flow along the respiratory chain to O₂ (CIV), which is linked to a proton flux from the mitochondrial matrix to the intermembranous space. Passage of protons back to the matrix through the ATPase complex drives ATP synthesis. ATP passes through the inner and outer mitochondrial membranes via the adenine nucleotide translocator (ANT) into cytosol. Under normal conditions, 1–2% of electron flow through the respiratory chain reduces O₂ to superoxide anion radical (O₂^·−) at complexes I and III. Hypoxia diverts more of the electron flow to O₂^·− production, with O₂^·−'s generated at complex III a major source of mitochondria-derived reactive oxygen species (ROS) in cytosol. The dashed lines show the reversal of membrane transport for protons and ATP in O₂ deficiency. ATP generated by cytosolic glycolysis is carried into mitochondria, where it is hydrolyzed by ATPase. This supplies energy for the extrusion of protons from the mitochondrial matrix to the intermembranous space to maintain the mitochondrial membrane potential. [Adapted from Solaini et al. (317).]