| Iron is an essential micronutrient that serves as a co-factor in a variety of enzymes with functions in gas exchange, energy production, protein synthesis, DNA repair and replication, antioxidant defenses, and more. However, iron is extremely toxic when present in excess, and so its levels must be tightly controlled inside individual organelles, cells and tissues. Our understanding of how iron balance is maintained is very limited. For example, little is known about how iron is shuttled between the cytosol and mitochondria for the formation of heme and iron-sulfur (Fe/S) clusters. Here, we identify mitochondrial ATP-binding cassette protein B8 (ABCB8) as a facilitator of iron export from the mitochondria, required for a baseline cardiac function and maturation of cytosolic Fe/S proteins. We also show that ABCB10, another mitochondrial transporter with unknown function, is involved in export of delta-aminolevulinic acid (ALA), a precursor of heme, disputing a commonly-stated hypothesis that this protein functions as a heme exporter.;Regulation of cellular iron homeostasis was shown to depend on the activity of iron regulatory proteins 1/2 (IRP1/2) and modulation of mRNA stability of key iron transporters. Our studies identify a parallel iron regulatory network mediated by the mammalian target of rapamycin (mTOR) and tristetraprolin (TTP), which regulate expression of transferrin receptor 1 (TfR1), a cellular iron importer. Induction of TTP by rapamycin (an inhibitor of mTOR) results in destabilization of TfR1 mRNA and reduction in cellular iron import. Moreover, TTP conserves cellular iron by repressing non-essential iron-requiring proteins and thus sparing iron for vital processes.;Finally, we examine how iron balance is altered in heart failure, a common and presently incurable human disease associated with increased oxidative stress and disruption of mitochondrial function. We find that mitochondrial iron levels are increased in failing hearts. Moreover, we observe a pronounced induction of heme synthesis, likely through a hypoxia-mediated upregulation of gamma aminolevulinic acid synthase 2 (ALAS2), a rate-limiting enzyme in this pathway. Taken together, this work presents novel and important findings in iron regulation in mitochondria, whole cell, and a systemic pathologic condition. |
