MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU.
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.
Favaro
Elena
E
Genomics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Ramachandran
Anassuya
A
McCormick
Robert
R
Gee
Harriet
H
Blancher
Christine
C
Crosby
Meredith
M
Devlin
Cecilia
C
Blick
Christopher
C
Buffa
Francesca
F
Li
Ji-Liang
JL
Vojnovic
Borivoj
B
Pires das Neves
Ricardo
R
Glazer
Peter
P
Iborra
Francisco
F
Ivan
Mircea
M
Ragoussis
Jiannis
J
Harris
Adrian L
AL
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
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