MicroRNA-210 decreases heme levels by targeting ferrochelatase in cardiomyocytes.

Aijun Qiao*, Arineh Khechaduri, R. Kannan Mutharasan, Rongxue Wu, Varun Nagpal, Hossein Ardehali

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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. 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. Our results identify a role for miR-210 in the regulation of heme production by targeting and inhibiting FECH under normoxic conditions.

Original languageEnglish (US)
JournalUnknown Journal
Volume2
Issue number2
DOIs
StatePublished - Jan 1 2013

Fingerprint

Ferrochelatase
MicroRNAs
Heme
Cardiac Myocytes
Iron
sulofenur
3' Untranslated Regions
Binding Sites
Mutation
Proteins
Chelating Agents
Sulfur

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Qiao, Aijun ; Khechaduri, Arineh ; Kannan Mutharasan, R. ; Wu, Rongxue ; Nagpal, Varun ; Ardehali, Hossein. / MicroRNA-210 decreases heme levels by targeting ferrochelatase in cardiomyocytes. In: Unknown Journal. 2013 ; Vol. 2, No. 2.
@article{3149051f860c40c0b2c52dcc9b931e7a,
title = "MicroRNA-210 decreases heme levels by targeting ferrochelatase in cardiomyocytes.",
abstract = "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. 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. Our results identify a role for miR-210 in the regulation of heme production by targeting and inhibiting FECH under normoxic conditions.",
author = "Aijun Qiao and Arineh Khechaduri and {Kannan Mutharasan}, R. and Rongxue Wu and Varun Nagpal and Hossein Ardehali",
year = "2013",
month = "1",
day = "1",
doi = "10.1161/JAHA.113.000121",
language = "English (US)",
volume = "2",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "2",

}

MicroRNA-210 decreases heme levels by targeting ferrochelatase in cardiomyocytes. / Qiao, Aijun; Khechaduri, Arineh; Kannan Mutharasan, R.; Wu, Rongxue; Nagpal, Varun; Ardehali, Hossein.

In: Unknown Journal, Vol. 2, No. 2, 01.01.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MicroRNA-210 decreases heme levels by targeting ferrochelatase in cardiomyocytes.

AU - Qiao, Aijun

AU - Khechaduri, Arineh

AU - Kannan Mutharasan, R.

AU - Wu, Rongxue

AU - Nagpal, Varun

AU - Ardehali, Hossein

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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. 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. Our results identify a role for miR-210 in the regulation of heme production by targeting and inhibiting FECH under normoxic conditions.

AB - 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. 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. Our results identify a role for miR-210 in the regulation of heme production by targeting and inhibiting FECH under normoxic conditions.

UR - http://www.scopus.com/inward/record.url?scp=84883470946&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883470946&partnerID=8YFLogxK

U2 - 10.1161/JAHA.113.000121

DO - 10.1161/JAHA.113.000121

M3 - Article

VL - 2

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 2

ER -