The UQCC3 gene encodes a protein that functions in complex III assembly, downstream of assembly factors UQCC1 and UQCC2. This is evidenced by the observation that UQCC3 levels are reduced in cells with decreased levels of UQCC1 and UQCC2, but lack of the UQCC3 protein does not affect levels of UQCC1 and UQCC2.[3] Predicted to be a secretary protein with small molecular weight, this protein has important functions in cellular proliferation and antiviral innate immune regulation. Expression of this protein is ubiquitous in carcinomas, along with normal tissues.[7] During the early stages of Complex III assembly, the UQCC3 protein stabilizes supercomplexes containing Complex III, most notably the III2/IV supercomplex.
Clinical Significance
In the sole recorded case of a mutation in the UQCC3 gene, a patient with a homozygousmissense mutation presented with nuclear type 9 complex III deficiency, displaying symptoms of hypoglycemia, hypotonia, lactic acidosis, severe delayed psychomotor development, and other developmental delay. The patient also had decreased levels of cytochrome b within Complex III.[3]
The UQCC3 protein also has a role as an antiviral factor, independent of interferon production. Levels of this protein increase in response to a viral infection, improving the ability of cells to inhibit viral replication. Overexpression of the UQCC3 gene increases transcription of OAS3 while knockdown of RNase L or OAS3 hampers the antiviral effect of UQCC3. Signaling from UQCC3 to the OAS-RNase L system is independent of interferon production.[4] This protein is also regulated by expression of the double-stranded RNA-dependent protein kinase EIF2AK2.[7]
Depleted levels of the UQCC3 protein cause impaired respiration and subtle yet significant alterations in cardiolipin composition, which then result in abnormal crista morphology, increased sensitivity to apoptosis, and decreased levels of ATP. Furthermore, mitochondrial depolarization causes OMA1 metalloprotease to cleave the UQCC3 protein; effectively, this mechanism targets cells with damaged mitochondria for apoptosis.[2]
↑ 7.07.17.2Xiong SQ, Yang HS, Long QD (February 2010). "[Bioinformatics analysis and function prediction of the novel gene AY358935]". Nan Fang Yi Ke Da Xue Xue Bao = Journal of Southern Medical University. 30 (2): 232–5. PMID20159687.
Xiong SQ, Yang HS, Long QD (February 2010). "[Bioinformatics analysis and function prediction of the novel gene AY358935]". Nan Fang Yi Ke Da Xue Xue Bao = Journal of Southern Medical University (in Chinese). 30 (2): 232–5. PMID20159687.CS1 maint: Unrecognized language (link)
Wanschers BF, Szklarczyk R, van den Brand MA, Jonckheere A, Suijskens J, Smeets R, Rodenburg RJ, Stephan K, Helland IB, Elkamil A, Rootwelt T, Ott M, van den Heuvel L, Nijtmans LG, Huynen MA (December 2014). "A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability". Human Molecular Genetics. 23 (23): 6356–65. doi:10.1093/hmg/ddu357. PMID25008109.