title: MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU.
abstract: BACKGROUND
  Hypoxia in cancers results in the upregulation of hypoxia inducible factor 1 (HIF-1) and a microRNA, hsa-miR-210 (miR-210) which is associated with a poor prognosis.
  
  
  RESULTS
  In human cancer cell lines and tumours, we found that miR-210 targets the mitochondrial iron sulfur scaffold protein ISCU, required for assembly of iron-sulfur clusters, cofactors for key enzymes involved in the Krebs cycle, electron transport, and iron metabolism. Down regulation of ISCU was the major cause of induction of reactive oxygen species (ROS) in hypoxia. ISCU suppression reduced mitochondrial complex 1 activity and aconitase activity, caused a shift to glycolysis in normoxia and enhanced cell survival. Cancers with low ISCU had a worse prognosis.
  
  
  CONCLUSIONS
  Induction of these major hallmarks of cancer show that a single microRNA, miR-210, mediates a new mechanism of adaptation to hypoxia, by regulating mitochondrial function via iron-sulfur cluster metabolism and free radical generation.
authors.affiliation: Genomics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Favaro
authors.forename: Anassuya
authors.initials: A
authors.lastname: Ramachandran
authors.forename: Robert
authors.initials: R
authors.lastname: McCormick
authors.forename: Harriet
authors.initials: H
authors.lastname: Gee
authors.forename: Christine
authors.initials: C
authors.lastname: Blancher
authors.forename: Meredith
authors.initials: M
authors.lastname: Crosby
authors.forename: Cecilia
authors.initials: C
authors.lastname: Devlin
authors.forename: Christopher
authors.initials: C
authors.lastname: Blick
authors.forename: Francesca
authors.initials: F
authors.lastname: Buffa
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Li
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojnovic
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pires das Neves
authors.forename: Peter
authors.initials: P
authors.lastname: Glazer
authors.forename: Francisco
authors.initials: F
authors.lastname: Iborra
authors.forename: Mircea
authors.initials: M
authors.lastname: Ivan
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D042967:Electron Transport Complex I / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis
chemical_list: D005609:Free Radicals; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D042967:Electron Transport Complex I