Complex III, the Q cycle and Qp/Qn site inhibitors

Sousa and colleagues (2013) argued that the prokaryotes that invented cytochrome bc type respiratory chains probably also invented the Q-cycle¹. They described it as the membrane-phase, quinone-based analogue of flavin-based electron bifurcation, which had so far been seen only in the cytosol. In their proposed sequence of early energy conservation, it came last, after flavin-based bifurcation¹. Protasoni and Zeviani (2021) describe the mammalian enzyme as always dimeric. They report that every subunit is encoded in nuclear DNA except cytochrome b, which is encoded in mitochondrial DNA⁸. They also note that crystal structures of the bovine, chicken and yeast complexes have been resolved⁸.

Protasoni and Zeviani describe the Q-cycle as two parallel reactions that involve the heme groups of cytochrome c1 and cytochrome b and the 2Fe/2S cluster of the Rieske protein⁷. Brzezinski, Moe and Ädelroth (2021) give the route in more detail. Ubiquinol binds at QP, near the p side of the membrane. Its first electron goes to the iron-sulfur centre and then to cytochrome c1, and two protons are released on the p side⁵. The second electron passes through heme bL and heme bH to a quinone at QN, which forms a semiquinone⁵. Protasoni and Zeviani add that each cytochrome c binds only one electron and, once reduced, moves on to complex IV⁷.

Letts and colleagues (2019) tested the supercomplex I+III2 in amphipol. Myxothiazol, a QP-site inhibitor, and antimycin A, a QN-site inhibitor, both inhibited strongly, with Hill coefficients close to 2. The authors suggested that binding at either site in the dimer may be enough to inhibit complex III³. Their cryo-EM maps showed coenzyme Q-10 head-group density at both QN sites and at the QP site distal from the complex I Q-tunnel. The QP site proximal to the tunnel showed none. They took this to suggest different affinities between the QP sites of the two protomers⁴.

Brzezinski and colleagues discuss a suggestion that higher affinity for ubiquinone at QN prevents release of a semiquinone that would make superoxide. They disagree on three grounds. The difference in affinity for ubiquinone at the two sites is not directly related to the affinity of the semiquinone at those sites. The semiquinone is not released to the membrane. Its reaction with oxygen is more likely to occur in place, and it occurs at QP rather than QN. They suggest instead that the ubiquinone seen bound at QN reflects a higher affinity for the substrate ubiquinone at QN than for the product ubiquinone at QP. They note that all the structures were of the oxidized state of complex III⁶. Sousa and colleagues (2016) found only one unresolved iron-sulfur domain in the bovine respirasome. They concluded that the two complex III monomers do not activate in alternation and have different functions². Didaran and colleagues (2026) note cryo-EM structures of plant cytochrome b6f with quinones at the Qp site⁹.