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 in complex I and in complex III, to match the decrease in Fe/S-cluster availability. In the absence of TTP, levels are not decreased in iron deficiency, resulting in nonfunctional complex III, electron leakage, and oxidative damage. Mice with deletion of 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.

Background: Conserved Asp-137 destabilizes the hydrophobic core of the coiled-coil tropomyosin. Results: Leu substitution of Asp-137 decreases flexibility of tropomyosin and causes long range structural rearrangements; mouse hearts expressing this variant show altered function. Conclusion: Residue Asp-137 is important for regulatory function of tropomyosin in the heart. Significance: Our data support the hypothesis that tropomyosin flexibility regulates cardiac function in vivo.

In this review, we address the following question: Are modifications at the level of sarcomeric proteins in acquired heart failure early inducers of altered cardiac dynamics and signaling leading to remodeling and progression to decompensation? There is no doubt that most inherited cardiomyopathies are caused by mutations in proteins of the sarcomere. We think this linkage indicates that early changes at the level of the sarcomeres in acquired cardiac disorders may be significant in triggering the progression to failure. We consider evidence that there are rate-limiting mechanisms downstream of the trigger event of Ca2+ binding to troponin C, which control cardiac dynamics. We discuss new perspectives on how modifications in these mechanisms may be of relevance to redox signaling in diastolic heart failure, to angiotensin II signaling via β-arrestin, and to remodeling related to altered structural rigidity of tropomyosin. We think that these new perspectives provide a rationale for future studies directed at a more thorough understanding of the question driving our review.

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Introduction: Type II diabetes mellitus (T2DM) is a growing health problem affecting over 29 million Americans and individuals with T2DM have increased mortality after myocardial infarction and stroke. Thus, it is imperative to find novel treatments for diabetes to offset the increased risk of cardiovascular disease (CVD) related mortality. Tristetraprolin (TTP) is an mRNA binding protein first identified as an insulin responsive gene. It binds to AU-rich elements (AREs) in the 3’ untranslated region (UTR) of certain transcripts and promotes their degradation. Reduced TTP expression has been observed in human patients with obesity and insulin resistance, and computational analysis suggests that TTP may bind to and degrade the mRNA of key enzymes involved in glucose oxidation. Thus, we hypothesized that downregulation of TTP would increase glucose oxidation and protect against T2DM. Results: We found hepatic expression of TTP to be decreased in diabetic mice. Using an in silico analysis to identify mRNAs that are targeted by TTP and play a role in glucose metabolism, we identified the pyruvate dehydrogenase-E2 subunit (PDH-E2) to contain several conserved TTP binding sites in its 3’ UTR. PDH-E2 expression was significantly increased (mRNA > 1.4-fold; protein > 2-fold) in hepatocytes isolated from liver-specific TTP knockout (KO) mice. Furthermore, measurement of PDH-E2 mRNA stability showed that PDH-E2 mRNA is significantly stabilized with TTP deletion, indicating that TTP regulates PDH-E2 mRNA. We then assessed whether the regulation of PDH-E2 by TTP alters glucose metabolism. Using Seahorse, we found a 1.7-fold increase in oxidative metabolism in TTP KO cells fed with glucose and pyruvate. This increase was reversed with siRNA mediated downregulation of PDH-E2. Systemically, liver-specific TTP KO mice fed a high-fat diet had significantly lower blood glucose levels after glucose tolerance tests and insulin tolerance tests. Conclusion: Our results suggest that a decrease in TTP protects against the development of T2DM by increasing PDH-E2 expression and subsequent glucose oxidation in the liver. Together, these data provide a novel, potential therapeutic target for T2DM, a significant modifiable risk factor contributing to CVD mortality.