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Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):E6291-E6300. doi: 10.1073/pnas.1804701115. Epub 2018 Jun 18.

mRNA-binding protein tristetraprolin is essential for cardiac response to iron deficiency by regulating mitochondrial function.

Author information

1
Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
2
Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos, Consejo Superior de Investigaciones Científicas, 46980 Paterna, Valencia, Spain.
3
Departamento de Bioquímica y Biología Molecular, Universitat de València, 46100 Burjassot, Valencia, Spain.
4
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
5
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
6
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
7
Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; h-ardehali@northwestern.edu.

Abstract

Cells respond to iron deficiency by activating iron-regulatory proteins to increase cellular iron uptake and availability. However, it is not clear how cells adapt to conditions when cellular iron uptake does not fully match iron demand. Here, we show that the mRNA-binding protein tristetraprolin (TTP) is induced by iron deficiency and degrades mRNAs of mitochondrial Fe/S-cluster-containing proteins, specifically Ndufs1 in complex I and Uqcrfs1 in complex III, to match the decrease in Fe/S-cluster availability. In the absence of TTP, Uqcrfs1 levels are not decreased in iron deficiency, resulting in nonfunctional complex III, electron leakage, and oxidative damage. Mice with deletion of Ttp display cardiac dysfunction with iron deficiency, demonstrating that TTP is necessary for maintaining cardiac function in the setting of low cellular iron. Altogether, our results describe a pathway that is activated in iron deficiency to regulate mitochondrial function to match the availability of Fe/S clusters.

KEYWORDS:

cardiomyopathy; iron; mRNA-binding protein; mitochondrial complex; reactive oxygen species

PMID:
29915044
PMCID:
PMC6142244
DOI:
10.1073/pnas.1804701115
[Indexed for MEDLINE]
Free PMC Article

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