Dihydro-orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction.

Abstract

Some mutations of the DHODH (dihydro-orotate dehydrogenase) gene lead to postaxial acrofacial dysostosis or Miller syndrome. Only DHODH is localized at mitochondria among enzymes of the de novo pyrimidine biosynthesis pathway. Since the pyrimidine biosynthesis pathway is coupled to the mitochondrial RC (respiratory chain) via DHODH, impairment of DHODH should affect the RC function. To investigate this, we used siRNA (small interfering RNA)-mediated knockdown and observed that DHODH knockdown induced cell growth retardation because of G₂/M cell-cycle arrest, whereas pyrimidine deficiency usually causes G₁/S arrest. Inconsistent with this, the cell retardation was not rescued by exogenous uridine, which should bypass the DHODH reaction for pyrimidine synthesis. DHODH depletion partially inhibited the RC complex III, decreased the mitochondrial membrane potential, and increased the generation of ROS (reactive oxygen species). We observed that DHODH physically interacts with respiratory complexes II and III by IP (immunoprecipitation) and BN (blue native)/SDS/PAGE analysis. Considering that pyrimidine deficiency alone does not induce craniofacial dysmorphism, the DHODH mutations may contribute to the Miller syndrome in part through somehow altered mitochondrial function.

• Authors: JingXian Fang, Takeshi Uchiumi, Mikako Yagi, Shinya Matsumoto, Rie Amamoto, Shinya Takazaki, Haruyoshi Yamaza, Kazuaki Nonaka, Dongchon Kang
• Journal: Bioscience reports (Biosci Rep) Vol. 33 Issue 2 Pg. e00021 (Feb 05 2013) ISSN: 1573-4935 [Electronic] England
• PMID: 23216091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dihydroorotate Dehydrogenase
• Pyrimidines
• RNA, Small Interfering
• Reactive Oxygen Species
• respiratory complex II
• Ubiquinone
• Oxidoreductases Acting on CH-CH Group Donors
• Electron Transport Complex II
• pyrimidine

Topics

• Abnormalities, Multiple (etiology, genetics, pathology)
• Dihydroorotate Dehydrogenase
• Electron Transport Complex II (genetics, metabolism)
• HeLa Cells
• Humans
• Limb Deformities, Congenital (etiology, genetics, pathology)
• Mandibulofacial Dysostosis (etiology, genetics, pathology)
• Membrane Potential, Mitochondrial (genetics)
• Micrognathism (etiology, genetics, pathology)
• Mitochondria (genetics, pathology)
• Mutation
• Oxidative Phosphorylation
• Oxidoreductases Acting on CH-CH Group Donors (genetics, metabolism)
• Pyrimidines (biosynthesis)
• RNA, Small Interfering (genetics)
• Reactive Oxygen Species (metabolism)
• Ubiquinone (metabolism)