MicroRNA-210 Regulates Mitochondrial Free Radical Response to Hypoxia and Krebs Cycle in Cancer Cells by Targeting Iron Sulfur Cluster Protein ISCU

Elena Favaro,Harriet Gee,Christine Blancher,Mircea Ivan,Ji-Liang Li,Francisco Iborra,Peter Glazer,Francesca Buffa,Anassuya Ramachandran,Ricardo Pires Das Neves,Jiannis Ragoussis,Cecilia Devlin,Borivoj Vojnovic,Christopher Blick,Robert Mccormick,Adrian L Harris,Meredith Crosby

doi:10.1371/journal.pone.0010345

Abstract

BackgroundHypoxia 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.Methods and FindingsIn 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.ConclusionsInduction 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.

Highlights

Hypoxia is a major physiological difference between tumours and normal tissue, mainly generated by tumour growth with inadequate blood supply and consumption of oxygen by tumour cells [reviewed in [1]]
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
Selection of ISCU as a potential target We compared miR-210 expression in our published series of breast cancer [14] with our hypoxia metagene of clustered mRNAs [25] and combined assessment with target prediction algorithms showed ISCU was the highest predicted target, and three known target genes sit in highly-ranked positions were selected by this approach (Supporting Material and Methods S1, Supporting Table S1)

Summary

Introduction

Hypoxia is a major physiological difference between tumours and normal tissue, mainly generated by tumour growth with inadequate blood supply and consumption of oxygen by tumour cells [reviewed in [1]]. Hypoxia induces a complex transcriptional response mainly via induction of hypoxia inducible factor 1a (HIF1a), affecting many biological processes such as the glycolytic pathway, angiogenesis, pH regulation, invasion and immortalisation [2]. An emerging paradigm in hypoxia is that mitochondria produce reactive oxygen species, mediated by electron transport continuing in hypoxia [3]. This free radical pathway contributes to upregulation of HIF [4] and enhanced growth in vivo [5], yet may be toxic. Hypoxia in cancers results in the upregulation of hypoxia inducible factor 1 (HIF-1) and a microRNA, hsa-miR210 (miR-210) which is associated with a poor prognosis

Methods

Results

Conclusion