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 language | English (US) |
|---|---|
| Pages (from-to) | E6291-E6300 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 115 |
| Issue number | 27 |
| DOIs | |
| State | Published - Jul 3 2018 |
Funding
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We thank Kai Xu, Meng Shang, and Eric Xia for genotyping and animal husbandry; Arineh Khechaduri for technical help; and Lisa Wilsbacher and Paul Burridge for critical suggestions on the paper. This work was supported by NIH Grants R01 HL127646, HL140973, and HL138982 (to H.A.), a predoctoral contract from the Spanish Ministry of Economy, Industry and Competitiveness (Mineco) (L.R.-A.), Mineco Grants BIO2014-56298-P and BIO2017-87828-C2-1-P and the European Regional Development Fund (S.P.), and Grant AICO/2015/004 from the Generalitat Valenciana (to M.T.M.-P.). Metabolomics studies were performed by the Metabolomics Core Facility at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Electron microscopy was performed at the Northwestern University Center for Advanced Microscopy generously supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. 21. 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We thank Kai Xu, Meng Shang, and Eric Xia for genotyping and animal husbandry; Arineh Khechaduri for technical help; and Lisa Wilsbacher and Paul Burridge for critical suggestions on the paper. This work was supported by NIH Grants R01 HL127646, HL140973, and HL138982 (to H.A.), a predoctoral contract from the Spanish Ministry of Economy, Industry and Competitiveness (Mineco) (L.R.-A.), Mineco Grants BIO2014-56298-P and BIO2017-87828-C2-1-P and the European Regional Development Fund (S.P.), and Grant AICO/2015/004 from the Generalitat Valenciana (to M.T.M.-P.). Metabolomics studies were performed by the Metabolomics Core Facility at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Electron microscopy was performed at the Northwestern University Center for Advanced Microscopy generously supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. ACKNOWLEDGMENTS. We thank Kai Xu, Meng Shang, and Eric Xia for genotyping and animal husbandry; Arineh Khechaduri for technical help; and Lisa Wilsbacher and Paul Burridge for critical suggestions on the paper. This work was supported by NIH Grants R01 HL127646, HL140973, and HL138982 (to H.A.), a predoctoral contract from the Spanish Ministry of Economy, Industry and Competitiveness (Mineco) (L.R.-A.), Mineco Grants BIO2014-56298-P and BIO2017-87828-C2-1-P and the European Regional Development Fund (S.P.), and Grant AICO/2015/004 from the Generalitat Valenciana (to M.T.M.-P.). Metabolomics studies were performed by the Metabolomics Core Facility at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Electron microscopy was performed at the Northwestern University Center for Advanced Microscopy generously supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.
Keywords
- Cardiomyopathy
- Iron
- Mitochondrial complex
- Reactive oxygen species
- mRNA-binding protein
ASJC Scopus subject areas
- General