title: A mutation in the mitochondrial protein UQCRB promotes angiogenesis through the generation of mitochondrial reactive oxygen species.
abstract: Ubiquinol-cytochrome c reductase binding protein (UQCRB) is one of the subunits of mitochondrial complex III and is a target protein of the natural anti-angiogenic small molecule terpestacin. Previously, the biological role of UQCRB was thought to be limited to the maintenance of complex III. However, the identification and validation of UQCRB as a target protein of terpestacin enabled the role of UQCRB in oxygen sensing and angiogenesis to be elucidated. To explore the biological role of this protein further, UQCRB mutant stable cell lines were generated on the basis of a human case report. We demonstrated that these cell lines exhibited glycolytic and pro-angiogenic activities via mitochondrial reactive oxygen species (mROS)-mediated HIF1 signal transduction. Furthermore, a morphological abnormality in mitochondria was detected in UQCRB mutant stable cell lines. In addition, the proliferative effect of the UQCRB mutants was significantly regulated by the UQCRB inhibitors terpestacin and A1938. Collectively, these results provide a molecular basis for UQCRB-related biological processes and reveal potential key roles of UQCRB in angiogenesis and mitochondria-mediated metabolic disorders.
authors.affiliation: Chemical Genomics National Research Lab., Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science & Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Junghwa
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Pharmaceutical Engineering, Sun Moon University, Asansi, Chungnam 330-150, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jung
authors.affiliation: National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Department of Health Sciences and Technology, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea.
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Jeong
authors.affiliation: National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Department of Health Sciences and Technology, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea.
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
authors.affiliation: National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Department of Health Sciences and Technology, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.affiliation: Chemical Genomics National Research Lab., Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science & Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea. Electronic address: kwonhj@yonsei.ac.kr.
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001483:Base Sequence; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D003001:Cloning, Molecular; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009389:Neovascularization, Pathologic; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001643:Bridged Bicyclo Compounds; D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C027208:ubiquinone-binding proteins; C080890:terpestacin; D019344:Lactic Acid; D000255:Adenosine Triphosphate
keywords: Angiogenesis; Complex III; Mitochondria; Mitochondrial reactive oxygen species; UQCRB