cytochrome bc1 complex

**Location and structure:** Complex III sits in the inner mitochondrial membrane and functions as a dimer. Each monomer has 11 subunits. Three subunits carry the redox centers: cytochrome b (two heme b groups, b_L and b_H), cytochrome c1 (heme c1), and the Rieske iron-sulfur protein (2Fe-2S cluster). Cytochrome b is the only subunit encoded by mitochondrial DNA. The rest are nuclear-encoded.

**Function:** Complex III oxidizes ubiquinol (reduced CoQ, QH2) and reduces cytochrome c, a soluble one-electron carrier in the intermembrane space. Electron flow is Complex I or II → CoQ → Complex III → cytochrome c → Complex IV. The reaction is QH2 + 2 cyt c (Fe3+) → Q + 2 cyt c (Fe2+) + 2 H+ (net, pumped).

**The Q cycle:** CoQ carries 2 electrons, but cytochrome c carries only 1, so the complex uses a bifurcated mechanism. - At the Qo (outer) site, QH2 is oxidized. One electron goes to the Rieske Fe-S, then to cyt c1, then to cyt c. The second electron goes to heme b_L, then to heme b_H, then to Qi. Two protons are released into the intermembrane space. - At the Qi (inner) site, Q is reduced to a semiquinone, then to QH2 with a second round, taking up 2 protons from the matrix. - Net result: 4 H+ are released into the intermembrane space per QH2 oxidized, 2 of them substrate protons and 2 pumped. Two electrons reach cytochrome c, and 2 matrix protons are consumed. The proton gradient drives ATP synthase (Complex V).

**Inhibitors (high-yield):** - Antimycin A blocks the Qi site. It is a classic board answer, and it causes a "crossover" with reduced upstream carriers and oxidized downstream ones. - Myxothiazol and stigmatellin block the Qo site. - Atovaquone, a ubiquinone analog, selectively inhibits the parasite's cytochrome bc1. It is used for malaria (atovaquone-proguanil) and for Pneumocystis jirovecii and Babesia. Resistance arises from cytochrome b mutations. - Complex III inhibition leaves the ETC reduced upstream. Oxygen consumption falls, ATP synthesis falls, and ROS rise. - Other ETC inhibitors, for contrast: - Complex I: rotenone, amytal, metformin. - Complex II: malonate, carboxin. - Complex IV: cyanide, carbon monoxide, azide, H2S. - Complex V: oligomycin. - Uncouplers (2,4-DNP, thermogenin/UCP1, aspirin overdose) dissipate the gradient.

**Clinical associations:** - Mutations in the mtDNA gene MT-CYB cause exercise intolerance, myopathy, and occasionally cardiomyopathy or multisystem disease. Mitochondrial inheritance is maternal, with heteroplasmy. - Nuclear BCS1L mutations (a Complex III assembly factor) cause GRACILE syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, early death) and Björnstad syndrome (pili torti with sensorineural hearing loss). - Complex III deficiency generally presents with lactic acidosis, myopathy, and encephalopathy. - Complex III is a major site of superoxide (ROS) generation, via the unstable semiquinone at Qo. - Some fungicides, such as strobilurins, target Complex III.

**Memory aids:** "Antimycin A → Complex III." Cytochromes carry electrons via heme iron cycling Fe3+/Fe2+, whereas CoQ is a mobile lipid-soluble carrier. Cytochrome c also triggers apoptosis when released into the cytosol, where it binds Apaf-1 to form the apoptosome and activates caspase-9.