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Tristetraprolin-mediated Regulation of Rieske, a Mitochondrial Complex III Protein, Protects the Heart Against Iron Deficiency

      Background: Iron deficiency plays a role in aggravation of heart failure. We recently found that tristetraprolin (TTP), a protein binding to and degrading mRNAs, is activated in iron-deprived cardiomyocytes. Here, we examined a hypothesis that TTP protects the heart under iron deficiency by regulating the expression of proteins associated with mitochondrial electron transport chain complex. Methods and Results: In TTP-KO mice, but not in wild type mice, iron deficiency by low iron diet induced significant cardiac dysfunction (LVFS: 25.8% vs. 31.6%), ultimately promoting development of cardiomyopathy. Unbiased in silico screening identified twenty-four genes containing the TTP-binding sequence. Iron chelation downregulated the level of UQCRFS1, one of the twenty-four mRNAs, in cardiomyocytes by 40%, but the downregulation was canceled by TTP deletion. Under iron deficiency, the level of Rieske, a UQCRFS1-encoded complex III protein containing iron-sulfur cluster, was preserved in TTP-deficient cells, albeit in an iron-sulfur cluster-deficient form (Apo-Rieske). Blue-native PAGE revealed that Apo-Rieske was incorporated into complex III in the absence of TTP under iron deficiency, leading to excess leakage of ROS at complex III. Conclusions: The results suggest that TTP plays a role in adaptive response to iron deficiency by optimizing expression level of Rieske. Increased incorporation of Apo-Rieske into complex III and subsequent ROS production in the absence of TTP may underlie development of iron deficiency-mediated cardiomyopathy.
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