MicroRNA-210 decreases heme levels by targeting ferrochelatase in cardiomyocytes.
J Am Heart Assoc
; 2(2): e000121, 2013 Apr 22.
Article
em En
| MEDLINE
| ID: mdl-23608607
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. METHODS ANDRESULTS:
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Miócitos Cardíacos
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Mioblastos Cardíacos
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MicroRNAs
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Ferroquelatase
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Heme
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Ferro
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Hipóxia
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article