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Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression

Abstract

The mechanisms of compromised mitochondrial function under various pathological conditions, including hypoxia, remain largely unknown. Recent studies have shown that microRNA-210 (miR-210) is induced by hypoxia under the regulation of hypoxia-inducible factor-1α and has an important role in cell survival under hypoxic microenvironment. Hence, we hypothesized that miR-210 has a role in regulating mitochondrial metabolism and investigated miR-210 effects on mitochondrial function in cancer cell lines under normal and hypoxic conditions. Our results demonstrate that miR-210 decreases mitochondrial function and upregulates the glycolysis, thus make cancer cells more sensitive to glycolysis inhibitor. miR-210 can also activate the generation of reactive oxygen species (ROS). ISCU (iron-sulfur cluster scaffold homolog) and COX10 (cytochrome c oxidase assembly protein), two important factors of the mitochondria electron transport chain and the tricarboxylic acid cycle have been identified as potential targets of miR-210. The unique means by which miR-210 regulates mitochondrial function reveals an miRNA-mediated link between microenvironmental stress, oxidative phosphorylation, ROS and iron homeostasis.

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References

  • Bristow RG, Hill RP . (2008). Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8: 180–192.

    Article  CAS  PubMed  Google Scholar 

  • Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP et al. (1998). Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282: 1497–1501.

    Article  CAS  PubMed  Google Scholar 

  • Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H et al. (2008). hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res 14: 1340–1348.

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Lu W, Garcia-Prieto C, Huang P . (2007). The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr 39: 267–274.

    Article  CAS  PubMed  Google Scholar 

  • Crosby ME, Kulshreshtha R, Ivan M, Glazer PM . (2009). MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Res 69: 1221–1229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diaz F, Fukui H, Garcia S, Moraes CT . (2006). Cytochrome c oxidase is required for the assembly/stability of respiratory complex I in mouse fibroblasts. Mol Cell Biol 26: 4872–4881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giannakakis A, Sandaltzopoulos R, Greshock J, Liang S, Huang J, Hasegawa K et al. (2008). miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer. Cancer Biol Ther 7: 255–264.

    Article  CAS  PubMed  Google Scholar 

  • Greither T, Grochola L, Udelnow A, Lautenschlager C, Wurl P, Taubert H . (2010). Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumours associates with poorer survival. Int J Cancer 126: 73–80.

    Article  CAS  PubMed  Google Scholar 

  • Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD et al. (2005). Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1: 401–408.

    Article  CAS  PubMed  Google Scholar 

  • Hsu PP, Sabatini DM . (2008). Cancer cell metabolism: Warburg and beyond. Cell 134: 703–707.

    Article  CAS  PubMed  Google Scholar 

  • Johnson DC, Dean DR, Smith AD, Johnson MK . (2005). Structure, function, and formation of biological iron-sulfur clusters. Annu Rev Biochem 74: 247–281.

    Article  CAS  PubMed  Google Scholar 

  • Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ et al. (2007). A microRNA signature of hypoxia. Mol Cell Biol 27: 1859–1867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K et al. (2008). Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol 141: 672–675.

    Article  PubMed  Google Scholar 

  • Lee YS, Dutta A . (2009). MicroRNAs in cancer. Annu Rev Pathol 4: 199–227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luthra R, Singh RR, Luthra MG, Li YX, Hannah C, Romans AM et al. (2008). MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers. Oncogene 27: 6667–6678.

    Article  CAS  PubMed  Google Scholar 

  • Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC . (2006). HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3: 187–197.

    Article  CAS  PubMed  Google Scholar 

  • Pelicano H, Feng L, Zhou Y, Carew JS, Hileman EO, Plunkett W et al. (2003). Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem 278: 37832–37839.

    Article  CAS  PubMed  Google Scholar 

  • Tong WH, Rouault TA . (2006). Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis. Cell Metab 3: 199–210.

    Article  CAS  PubMed  Google Scholar 

  • Trachootham D, Alexandre J, Huang P . (2009). Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8: 579–591.

    Article  CAS  PubMed  Google Scholar 

  • Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN et al. (2005). Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 65: 613–621.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dawn Chalaire for critical editing of the article.

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Correspondence to R Luthra.

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Chen, Z., Li, Y., Zhang, H. et al. Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression. Oncogene 29, 4362–4368 (2010). https://doi.org/10.1038/onc.2010.193

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  • DOI: https://doi.org/10.1038/onc.2010.193

Keywords

  • miR-210
  • mitochondria
  • hypoxia
  • COX10
  • ISCU
  • ROS

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