A mutation in the mitochondrial protein UQCRB promotes angiogenesis through the generation of mitochondrial reactive oxygen species

Biochem Biophys Res Commun. 2014 Dec 12;455(3-4):290-7. doi: 10.1016/j.bbrc.2014.11.005. Epub 2014 Nov 11.

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.

Keywords: Angiogenesis; Complex III; Mitochondria; Mitochondrial reactive oxygen species; UQCRB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Base Sequence
  • Bridged Bicyclo Compounds / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Proliferation
  • Cloning, Molecular
  • Enzyme-Linked Immunosorbent Assay
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lactic Acid / metabolism
  • Microscopy, Electron, Transmission
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Molecular Sequence Data
  • Mutation
  • Neovascularization, Pathologic*
  • Oxygen Consumption
  • Reactive Oxygen Species / metabolism*
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Bridged Bicyclo Compounds
  • Carrier Proteins
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • ubiquinone-binding proteins
  • terpestacin
  • Lactic Acid
  • Adenosine Triphosphate