Abstract 15716: Tristetraprolin Protects the Heart Against Iron Deficiency by Reducing Expression of Iron-requiring Proteins and Optimizing Cellular Iron Utilization
Background: Iron deficiency is the most common nutrient deficiency in the world, however, patients with severe iron deficiency generally have normal cardiac function. This suggests that a mechanism exists in the heart that maintains cardiac iron levels despite systemic iron deficiency, however, the mechanism for this adaptation of the heart to iron deficiency is not known. We recently discovered an mRNA-binding protein tristetraprolin (TTP) to mediate iron utilization within an iron-deprived cell independently of the canonical iron regulatory proteins (IRPs). Here, we hypothesized that TTP protects the heart against iron deficiency through intracellular conservation of iron, and that disruption of this pathway will make the heart vulnerable to low-iron states.
Results: Consistent with the above hypothesis, we demonstrated that hearts of TTP knockout mice have normal baseline function, yet deteriorate when subjected to iron deficiency. On contrary, iron-deficient TTP WT mice show no decline in cardiac function in spite of significant reduction in iron levels. Since TTP is known to reduce protein expression through mRNA degradation, we hypothesized that it halts expression of iron-consuming proteins, reducing overall cardiomyocyte’s iron requirements. We identified three mitochondrial iron-requiring proteins to be negatively regulated by TTP: NDUFS1 (part of complex I), UQCRFS1 (part of complex III), and mitochondrial aconitase (part of the TCA cycle). Specifically, we showed that TTP binds to and degrades mRNAs of these targets. This is based on data that the steady state level of the mRNAs for these proteins are decreased with iron chelation, but do not change with TTP deletion. Additionally, mRNAs of these proteins are protected against after actinomycin-D treatment with TTP deletion. RNA co-immunoprecipitation studies confirmed TTP binding to the mRNAs of these proteins. Thus, in the absence of TTP, these proteins continue to be expressed and act as “iron sinks” in a cell that is already iron deficient.
Conclusions: Our results, for the first time, provide the mechanism of cellular adaptation to iron deficiency, and demonstrate a major role for TTP in this process by regulating mitochondrial proteins.
Author Disclosures: T. Sato: Research Grant; Modest; MWA Summer 2014 Postdoctoral Fellowship. M. Bayeva: None. H. Ardehali: None.
- © 2015 by American Heart Association, Inc.