title: MicroRNA-210 decreases heme levels by targeting ferrochelatase in cardiomyocytes.
abstract: BACKGROUND
  MicroRNA-210 (miR-210) increases in hypoxia and regulates mitochondrial respiration through modulation of iron-sulfur cluster assembly proteins (ISCU1/2), a protein that is involved in Fe/S cluster synthesis. However, it is not known how miR-210 affects cellular iron levels or production of heme, another iron containing molecule that is also needed for cellular and mitochondrial function.
  
  
  RESULTS
  To screen for micro-ribonucleic acids (miRNAs) regulated by iron, we performed a miRNA gene array in neonatal rat cardiomyocytes treated with iron chelators. Levels of miR-210 are significantly increased with iron chelation, however, this response was mediated entirely through the hypoxia-inducible factor (HIF) pathway. Furthermore, miR-210 reduced cellular heme levels and the activity of mitochondrial and cytosolic heme-containing proteins by modulating ferrochelatase (FECH), the last enzyme in heme biosynthesis. Mutation of the 2 miR-210 binding sites in the 3' untranslated region (UTR) of FECH reversed the miR-210 response, while mutation of either binding site in isolation did not exert any effects. Changes mediated by miR-210 in heme and FECH were independent of ISCU, as overexpression of an ISCU construct lacking the 3' UTR does not alter miR-210 regulation of heme and FECH. Finally, FECH levels increased in hypoxia, and this effect was not reversed by miR-210 knockdown, suggesting that the effects of miR-210 on heme are restricted to normoxic conditions, and that the pathway is overriden in hypoxia.
  
  
  CONCLUSIONS
  Our results identify a role for miR-210 in the regulation of heme production by targeting and inhibiting FECH under normoxic conditions.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago,IL 60611, USA.
authors.forename: Aijun
authors.initials: A
authors.lastname: Qiao
authors.forename: Arineh
authors.initials: A
authors.lastname: Khechaduri
authors.forename: R
authors.initials: R
authors.lastname: Kannan Mutharasan
authors.forename: Rongxue
authors.initials: R
authors.lastname: Wu
authors.forename: Varun
authors.initials: V
authors.lastname: Nagpal
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005294:Ferrochelatase / Q000378:metabolism*; D057809:HEK293 Cells; D006418:Heme / Q000096:biosynthesis*; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology; D007501:Iron / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D032386:Myoblasts, Cardiac / Q000201:enzymology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D051381:Rats
chemical_list: D051793:Hypoxia-Inducible Factor 1; C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; C543800:MIRN210 microRNA, human; C549325:MIRN210 microRNA, mouse; C546388:MIRN210 microRNA, rat; D035683:MicroRNAs; D006418:Heme; D007501:Iron; D005294:Ferrochelatase