# UQCRC2

## Overview
The UQCRC2 gene encodes the ubiquinol-cytochrome c reductase core protein II, which is a key component of the mitochondrial electron transport chain, specifically involved in complex III. This protein plays a crucial role in cellular energy production, facilitating the transfer of electrons from ubiquinol to cytochrome c, and is essential for the proper assembly and function of complex III. The UQCRC2 protein is integral to the mitochondrial membrane and contributes to the formation of the cytochrome bc1 complex, a vital element in oxidative phosphorylation and ATP synthesis. Mutations in the UQCRC2 gene can lead to mitochondrial complex III deficiency, affecting various metabolic processes and resulting in severe clinical manifestations (Burska2021Homozyous; Miyake2013Mitochondrial).

## Function
The UQCRC2 gene encodes the ubiquinol-cytochrome c reductase core protein II, a vital component of mitochondrial complex III (CIII) in the electron transport chain. This complex is integral to cellular energy production through oxidative phosphorylation, facilitating the transfer of electrons from ubiquinol to cytochrome c. The UQCRC2 protein plays a crucial role in the proper assembly and function of complex III, ensuring efficient energy production within cells (Burska2021Homozyous; Miyake2013Mitochondrial).

Complex III, also known as the cytochrome bc1 complex, is essential for the mitochondrial electron transport chain, which is crucial for generating ATP, the primary energy currency of the cell. The UQCRC2 subunit, along with UQCRC1, is involved in the dimerization of CIII during its early assembly phase, which is essential for the proper structural and functional integration of CIII into the mitochondrial membrane (Burska2021Homozygous).

Mutations in the UQCRC2 gene can lead to mitochondrial complex III deficiency, characterized by a range of metabolic disturbances such as hypoglycemia, lactic acidosis, ketosis, and hyperammonemia. These conditions underscore the critical role of UQCRC2 in maintaining the bioenergetics of a cell and supporting various metabolic processes (Miyake2013Mitochondrial).

## Clinical Significance
Mutations in the UQCRC2 gene, which encodes a core protein component of mitochondrial complex III, are associated with a spectrum of mitochondrial disorders, primarily affecting metabolic processes and neurological development. These mutations can lead to mitochondrial complex III deficiency, presenting with severe metabolic complications such as metabolic acidosis, hypoglycemia, hyperammonemia, and high lactate levels shortly after birth. The clinical manifestations include severe metabolic decompensation, recurrent hospitalizations, and complications like renal tubular acidosis and atrial septal defects (Miyake2013Mitochondrial).

The impact of UQCRC2 mutations varies among individuals. Some patients exhibit primarily metabolic symptoms without severe neurological deficits, while others suffer from significant neurodevelopmental issues, including Leigh-like syndrome, motor and cognitive delays, and encephalomyopathy (Abou2023Novel; Burska2021Homozygous). Notably, a specific mutation, p.Arg183Trp, has been shown to destabilize the hydrophobic core at the subunit interface of the core protein II homodimer, leading to impaired assembly of the mitochondrial supercomplex and reduced stability and expression of the mutant UQCRC2 protein (Miyake2013Mitochondrial).

In some cases, despite severe metabolic disturbances, patients maintain normal neurodevelopmental progress, highlighting the clinical variability associated with UQCRC2 mutations (Abou2023Novel). This variability necessitates personalized medical management strategies, including dietary modifications and supportive therapies tailored to the severity and nature of the symptoms presented by each patient.

## Interactions
UQCRC2, a core subunit of mitochondrial Complex III (CIII), forms a heterodimer with UQCRC1, which is essential for the early phase of CIII assembly and contributes to the matrix-exposed side of CIII. Both UQCRC1 and UQCRC2 share similar folding topologies and are anchored to the membrane by the N-terminal portion of UQCRC1. This interaction is critical for the proper assembly of CIII (Burska2021Homozygous). The Gly222Ala mutation in UQCRC2 disrupts its interaction with UQCRC1, leading to a failure in their stable association within the subassemblies of CIII and an accumulation of intermediates composed of various CIII structural subunits (Burska2021Homozygous). This mutation also impairs the interaction between complex I (CI) and CIII, affecting the electron flux from CI to CIII (Burska2021Homozygous). Additionally, UQCRC1 interacts with CI through a loop that is inserted into a groove formed by CI subunits NDUFB9 and NDU-FAB1, indicating a direct physical interaction between UQCRC2 (as part of the CIII) and CI within the mitochondrial respiratory chain supercomplexes (Burska2021Homozygous).


## References


[1. (Abou2023Novel) Lea Abou Haidar, Robert C. Harris, Panayotis Pachnis, Hongli Chen, Garrett K. Gotway, Min Ni, and Ralph J. DeBerardinis. Novel pathogenicuqcrc2variants in a female with normal neurodevelopment. Molecular Case Studies, 9(4):a006295, September 2023. URL: http://dx.doi.org/10.1101/mcs.a006295, doi:10.1101/mcs.a006295. (1 citations) 10.1101/mcs.a006295](https://doi.org/10.1101/mcs.a006295)

[2. (Miyake2013Mitochondrial) Noriko Miyake, Shoji Yano, Chika Sakai, Hideyuki Hatakeyama, Yuichi Matsushima, Masaaki Shiina, Yoriko Watanabe, James Bartley, Jose E. Abdenur, Raymond Y. Wang, Richard Chang, Yoshinori Tsurusaki, Hiroshi Doi, Mitsuko Nakashima, Hirotomo Saitsu, Kazuhiro Ogata, Yu-ichi Goto, and Naomichi Matsumoto. Mitochondrial complex iii deficiency caused by a homozygousuqcrc2mutation presenting with neonatal-onset recurrent metabolic decompensation. Human Mutation, 34(3):446–452, March 2013. URL: http://dx.doi.org/10.1002/humu.22257, doi:10.1002/humu.22257. (104 citations) 10.1002/humu.22257](https://doi.org/10.1002/humu.22257)

[3. (Burska2021Homozygous) Daniela Burska, Lukas Stiburek, Jana Krizova, Marie Vanisova, Vaclav Martinek, Jana Sladkova, Josef Zamecnik, Tomas Honzik, Jiri Zeman, Hana Hansikova, and Marketa Tesarova. Homozygous missense mutation in uqcrc2 associated with severe encephalomyopathy, mitochondrial complex iii assembly defect and activation of mitochondrial protein quality control. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1867(8):166147, August 2021. URL: http://dx.doi.org/10.1016/j.bbadis.2021.166147, doi:10.1016/j.bbadis.2021.166147. (14 citations) 10.1016/j.bbadis.2021.166147](https://doi.org/10.1016/j.bbadis.2021.166147)