UQCC3

Ubiquinol-cytochrome c reductase complex assembly factor 3 is a protein that in humans is encoded by the UQCC3 gene.[5] Located in mitochondria, this protein is involved in the assembly of mitochondrial Complex III, stabilizing supercomplexes containing Complex III.[6] Mutations in the UQCC3 gene cause Complex III deficiency with symptoms of hypoglycemia, hypotonia, lactic acidosis, and developmental delays.[7] This protein plays an important role as an antiviral factor, bolstering the ability of cells to inhibit viral replication, independent of interferon production.[8] The UQCC3 protein can be cleaved by OMA1 metalloprotease during mitochondrial depolarization, targeting the cell for apoptosis. Depletion of this protein alters cardiolipin composition, causing cellular and mitochondrial defects.[6]

UQCC3
Identifiers
Aliases	UQCC3, C11orf83, CCDS41658.1, UNQ655, MC3DN9, ubiquinol-cytochrome c reductase complex assembly factor 3
External IDs	OMIM: 616097 MGI: 2147553 HomoloGene: 84061 GeneCards: UQCC3
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q12.3 Start 62,670,273 bp[1] End 62,673,686 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19|19 A Start 8,880,014 bp[2] End 8,880,923 bp[2]
Gene ontology Molecular function • phosphatidic acid binding • cardiolipin binding Cellular component • mitochondrial respiratory chain complex III • mitochondrial inner membrane • integral component of membrane • membrane • mitochondrion • integral component of mitochondrial inner membrane Biological process • mitochondrial electron transport, ubiquinol to cytochrome c • cristae formation • ATP biosynthetic process • mitochondrial respiratory chain complex III assembly Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	790955	107197
Ensembl	ENSG00000204922	ENSMUSG00000071654
UniProt	Q6UW78	Q8K2T4
RefSeq (mRNA)	NM_001085372	NM_001160356
RefSeq (protein)	NP_001078841	NP_001153828
Location (UCSC)	Chr 11: 62.67 – 62.67 Mb	Chr 19: 8.88 – 8.88 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

The UQCC3 gene is located on the q arm of chromosome 11 in position 12.3 and spans 2,036 base pairs.[5] The gene produces a 10.1 kDa protein composed of 93 amino acids.[9][10] This protein faces the intermembrane space.[6] It possesses an N-terminal signal peptide and a signal transmembrane structure, in addition to several phosphorylation sites. The secondary structure of this protein is made up mostly of random coils and alpha helices.[11] Alpha helices 2 and 3 bind to cardiolipin.[6]

Function

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.[7] 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.[11] 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 homozygous missense 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.[7]

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.[8] This protein is also regulated by expression of the double-stranded RNA-dependent protein kinase EIF2AK2.[11]

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.[6]

Interactions

This protein associates with the rest of mitochondrial Complex III and has protein-protein interactions with PHLDA3.[12]

References

1. GRCh38: Ensembl release 89: ENSG00000204922 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000071654 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Ubiquinol-cytochrome c reductase complex assembly factor 3". Retrieved 2018-08-03.
6. Desmurs M, Foti M, Raemy E, Vaz FM, Martinou JC, Bairoch A, Lane L (April 2015). "C11orf83, a mitochondrial cardiolipin-binding protein involved in bc1 complex assembly and supercomplex stabilization". Molecular and Cellular Biology. 35 (7): 1139–56. doi:10.1128/MCB.01047-14. PMC 4355537. PMID 25605331.
7. 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. PMID 25008109.
8. Yang Y, Xiong S, Cai B, Luo H, Dong E, Li Q, Ji G, Zhao C, Wen Y, Wei Y, Yang H (April 2017). "Mitochondrial C11orf83 is a potent Antiviral Protein Independent of interferon production". Scientific Reports. 7: 44303. Bibcode:2017NatSR...744303Y. doi:10.1038/srep44303. PMC 5394693. PMID 28418037.
9. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
10. "UQCC3 - Ubiquinol-cytochrome-c reductase complex assembly factor 3". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
11. 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. 30 (2): 232–5. PMID 20159687.
12. "2 binary interactions found for search term UQCC3". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.

Further reading

• 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. PMID 20159687.
• 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. PMID 25008109.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.