*4.2. Complex III*

Complex III or the *bc1* complex is an integral inner membrane homodimeric complex of the mitochondrial inner membrane that catalyzes the oxidation of reduced coenzyme Q and reduction of cytochrome *c*, a reaction coupled to the translocation of protons from the matrix to the inter-membrane space [53]. Both human and yeast Complex III contain three catalytic subunits: a mitochondrially-encoded cytochrome *b*, with two non-covalently bound heme *b* containing redox centers corresponding to cytochromes *b*<sup>H</sup> and *b*L; cytochrome *c*1, with a covalently linked heme *b*; and the Rieske iron-sulfur protein [53–56]. In addition to the three catalytic subunits, Complex III contains seven other subunits, four of which are essential for the assembly and stability of the complex but do not participate in either electron transfer or proton translocation (Table 2). Like cytochrome *c*<sup>1</sup> and the Rieske iron sulfur protein, all the non-catalytic subunits are products of nuclear genes.

Assembly of Complex III also depends on nuclear encoded chaperones and on factors that regulate translation and assembly of cytochrome *b*. Most of the currently known Complex III assembly factors that were first described in yeast are conserved in humans (Table 2). Among yeast factors that have human homologs associated with diseases, there are Cbp6 and Cbp4. Cbp6, together with Cbp3, forms a complex with nascent apocytochrome *b* [57] for subsequent addition of heme to form the redox center at the cytochrome *b*<sup>L</sup> site, followed by stabilization of the partially mature protein by Cbp4 [58] and further hemylation of the cytochrome *b*<sup>H</sup> site [59]. Mitochondrial pathologies have also been reported in patients with mutations in human homologs of two other factors, Bcs1 and Mzm1, both needed for maturation and insertion of the Rieske iron sulfur protein into the complex [60–62].

Most laboratory strains of *S. cerevisiae* have a mitochondrial cytochrome *b* gene (*COB*) containing group I and II introns that are post-transcriptionally removed [63,64]. Some of the group II introns contain reading frames that code for factors, termed maturases, that function in splicing their own introns [65]. Splicing of the terminal group I intron is aided by a protein factor encoded by a nuclear gene [66]. In addition to these splicing factors, expression of *COB* depends on other factors that stabilize and activate translation of the mRNA [67,68]. Due to the absence of introns in the human cytochrome *b* gene and of 5′ - non-coding sequences in the human mRNA, none of the yeast RNA splicing factors and translational activators have human homologs.

Complex III disorders are relatively rare but, like mutations in the other respiratory complexes, they present a wide spectrum of phenotypes. Complex III deficiency can be caused by mutations in the mitochondrially-encoded cytochrome *b*, in nuclear genes coding for catalytic and structural subunits and in ancillary proteins that function in assembly of the complex.


**Table 2.** Yeast complex III subunits and their human homologs. The table also shows Complex III assembly factors that are associated with diseases.
