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

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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 27 Pg. E6291-E6300 (07 03 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 29915044 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Iron-Sulfur Proteins
• Tristetraprolin
• UQCRFS1 protein, mouse
• Zfp36 protein, mouse
• NADH Dehydrogenase
• NDUFS1 protein, mouse
• Electron Transport Complex III

Topics

• Animals
• Cell Line
• Electron Transport Complex III (genetics, metabolism)
• Iron Deficiencies
• Iron-Sulfur Proteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Mitochondria, Heart (enzymology, metabolism)
• Myocardium (metabolism)
• NADH Dehydrogenase (genetics, metabolism)
• Oxidation-Reduction
• Tristetraprolin (genetics, metabolism)