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

Tatsuya Sato, Hsiang Chun Chang, Marina Bayeva, Jason S. Shapiro, Lucia Ramos-Alonso, Hidemichi Kouzu, Xinghang Jiang, Ting Liu, Sumeyye Yar, Konrad T. Sawicki, Chunlei Chen, María Teresa Martínez-Pastor, Deborah J. Stumpo, Paul T Schumacker, Perry J. Blackshear, Issam Ben-Sahra, Sergi Puig, Hossein Ardehali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E6291-E6300
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number27
DOIs
StatePublished - Jul 3 2018

Keywords

  • Cardiomyopathy
  • Iron
  • Mitochondrial complex
  • Reactive oxygen species
  • mRNA-binding protein

ASJC Scopus subject areas

  • General

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