4.2.2. Mutations in Complex III Structural Subunits

A 4 bp deletion in *UQCRB* resulting in a change in the last seven amino acids and an addition of a stretch of 14 amino acids at the C-terminal end of the protein was the first described case of a Complex III deficiency resulting from mutations in a nuclear encoded subunit of the complex [74]. Interestingly, earlier studies on yeast Complex III showed that deletions in the C-terminal helical domain of the *QCR7* homolog resulted in reduced levels of the subunit and of cytochrome *b*, Rip1, and Qcr8 [75]. Taken together, these studies show the importance of the helical domain of *UQCRB* in the maintenance or assembly of human and yeast Complex III.

The discovery of the deletions in *UQCRB* was followed by the identification of a pathogenic variant of *UQCRQ* [76]. A pathogenic mutation in *UQCRC2* was also identified: three patients from a Mexican consanguineous family with neonatal onset of hypoglycemia and lactic acidosis were found to have a homozygous mutation leading to a R183W substitution in the Core 2 subunit. The patients also showed hyperammonemia, high urine organic acids and elevated plasma hydroxyl fatty acids, suggesting that the *UQCRC2* mutation may elicit secondary effects on TCA and urea cycles and beta-oxidation. Modeling of the crystal structure of bovine Complex III predicted that the R183W mutation would disrupt the hydrophobic interface of the UQCRC2 homodimer, leading to Complex III destabilization. This was supported by an 80% decrease of the complex in the patients, even though Complex III activity was only marginally affected [77]. More recently, the same homozygous mutation with similar symptoms was described in a French child [78]. Furthermore, the expression of *UQCRC2* is upregulated in multiple human tumors, whereas its suppression inhibits cancer cells and induces senescence [79].
