Abstract 12530: Tristetraprolin-mediated mRNA Degradation of Mitochondrial Electron Transport Chain Proteins Protects the Heart Against Iron Deficiency

Abstract

Introduction: Iron deficiency is the most common nutrient deficiency in the world, and cells respond to iron deficiency by activating iron regulatory proteins (IRP) to increase cellular iron uptake and availability. Although iron overload can cause cardiomyopathy, iron deficiency does not normally lead to cardiac damage. Tristetraprolin (TTP) is a tandem zinc finger protein that binds to the AU-rich elements (AREs) in the 3’ untranslated regions (UTR) of mRNA molecules and causes their degradation. We recently showed that TTP plays a role in iron conservation in the cell by targeting and degrading the mRNA for the iron importer, transferrin receptor 1. However, it is not clear how cells respond to conditions when cellular iron uptake and availability are not sufficient to match the demand. We hypothesized that TTP protects against cardiac dysfunction under iron deficiency by targeting the mRNAs of Fe/S cluster-containing proteins in the mitochondria. Results: To assess the effects of TTP on mitochondria, we first performed an unbiased in silico screen and identified a number of mRNAs that contain the consensus TTP-binding sequence in their 3’ UTR. Of those, steady-state levels of several mRNAs were increased with TTP deletion. However, only the mRNAs of three genes were shown to be bound by and be degraded by TTP protein: NDUFS1 in complex I, UQCRFS1 in complex III and mitochondrial aconitase. Interestingly, these proteins need Fe/S clusters to be active, suggesting that their protein levels are decreased in the absence of Fe/S cluster availability. We also demonstrate that in the absence of TTP and with iron deficiency, complex III gets formed with UQCRFS1, but without the required Fe/S cluster, which leads to the production of reactive oxygen species (ROS) and cellular injury. Finally, mice with systemic deletion of TTP display cardiac dysfunction under iron deficiency, demonstrating a major role for TTP in maintaining normal cellular function under iron deficiency. Conclusions: Our results provide a pathway that is activated in parallel to the IRPs and leads to degradation of mitochondrial mRNAs that require Fe/S clusters. This response to iron deficiency is critical to prevent excessive ROS production and cardiac damage.