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

Jing Xian Fang, Takeshi Uchiumi, Mikako Yagi, Shinya Matsumoto, Rie Amamoto, Shinya Takazaki, Haruyoshi Yamaza, Kazuaki Nonaka, Dongchon Kang

研究成果: ジャーナルへの寄稿記事

抄録

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.

元の言語英語
ジャーナルBioscience Reports
33
発行部数2
出版物ステータス出版済み - 2013

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Electron Transport
Biosynthesis
G2 Phase Cell Cycle Checkpoints
Native Polyacrylamide Gel Electrophoresis
dihydroorotate dehydrogenase
Mutation
Mitochondria
Mitochondrial Membrane Potential
Electron Transport Complex III
Uridine
Cell growth
Immunoprecipitation
Small Interfering RNA
Polyacrylamide Gel Electrophoresis
Reactive Oxygen Species
Genes
Cells
pyrimidine
Membranes
Enzymes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

これを引用

Dihydro-orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction. / Fang, Jing Xian; Uchiumi, Takeshi; Yagi, Mikako; Matsumoto, Shinya; Amamoto, Rie; Takazaki, Shinya; Yamaza, Haruyoshi; Nonaka, Kazuaki; Kang, Dongchon.

:: Bioscience Reports, 巻 33, 番号 2, 2013.

研究成果: ジャーナルへの寄稿記事

Fang, Jing Xian ; Uchiumi, Takeshi ; Yagi, Mikako ; Matsumoto, Shinya ; Amamoto, Rie ; Takazaki, Shinya ; Yamaza, Haruyoshi ; Nonaka, Kazuaki ; Kang, Dongchon. / Dihydro-orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction. :: Bioscience Reports. 2013 ; 巻 33, 番号 2.
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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.",
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AU - Fang, Jing Xian

AU - Uchiumi, Takeshi

AU - Yagi, Mikako

AU - Matsumoto, Shinya

AU - Amamoto, Rie

AU - Takazaki, Shinya

AU - Yamaza, Haruyoshi

AU - Nonaka, Kazuaki

AU - Kang, Dongchon

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