FIGURE 12-24 The Q cycle. The Q cycle of complex III uses the net oxidation of one CoQH₂ molecule to transfer four protons into the intermembrane space and two electrons to two cytochrome c molecules. The cycle begins when a molecule from the combined pool of reduced CoQH₂ in the inner mitochondrial membrane binds to the Q_o site on the intermembrane space (exoplasmic) side of the transmembrane portion of complex III (step 1). There CoQH₂ releases two protons into the intermembrane space (step 2a), and two electrons and the resulting CoQ dissociate (step 3). One of the electrons is transported, via an iron-sulfur protein and cytochrome c₁, directly to cytochrome c (step 2b). (Recall that each cytochrome c shuttles one electron from complex III to complex IV.) The other electron moves through cytochromes b_L and b_H and partially reduces an oxidized CoQ molecule bound to the second, Q_i, site on the matrix (cytosolic) side of the complex, forming a CoQ semiquinone anion, Q^•− (step 4). The process is repeated with the binding of a second CoQH₂ at the Q_o site (step 5), proton release (step 6a), reduction of another cytochrome c (step 6b), and addition of the other electron to the Q^•− bound at the Q_i site (step 7). There the addition of two protons from the matrix yields a fully reduced CoQH₂ molecule at the Q_i site, which then dissociates (steps 8 and 9), freeing the Q_i to bind a new molecule of CoQ (step 10) and begin the Q cycle over again. See B. Trumpower, 1990, J. Biol. Chem. 265:11409, and E. Darrouzet et al., 2001, Trends Biochem. Sci. 26:445.