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Cellular iron metabolism: mitochondria in the spotlight

Christopher R. Chitambar

Comment on Nie et al, page 2161, and Napier et al, page 1867

New insights into cellular iron metabolism have been provided by the recognition that certain diseases are associated with mitochondrial iron overload and by the discovery of mitochondrial ferritin (MtFt) and mitochondrial iron transporters.

There is no doubt that the handling of iron by the cell is a complex process. On one hand, iron deficiency may result in cessation of hemoglobin synthesis in erythroid cells and in induction of apoptosis in both erythroid and nonerythroid cells.1 On the other hand, iron excess, by catalyzing the generation of cytotoxic reactive oxygen species (ROSs), may also be detrimental to cells.2 The challenge facing a cell, therefore, is to incorporate from its environment an amount of iron sufficient to meet its metabolic needs and to be capable of protecting itself from the toxicity of excess intracellular iron. The former is achieved by transferrin receptor-1 (TfR1)–dependent or –independent iron uptake at the cell surface, while the latter is accomplished by sequestering intracellular iron in ferritin, the iron storage protein shell composed of 24 subunits of H- and L-ferritin chains.3 TfR1 and cytoplasmic ferritin syntheses are controlled by iron regulatory proteins (IRP1 and IRP2) that function as cytoplasmic sensors of cellular iron status. These IRPs regulate the translation of TfR1 and ferritin mRNAs through their interaction with iron regulatory elements (IREs) present on the untranslated regions of the respective mRNAs.4

The importance of iron in mitochondrial function is well known. However, the role of mitochondrial iron trafficking in the regulation of cellular iron homeostasis is not understood. In mitochondria, iron is used for the synthesis of heme and the generation of iron-sulfur [Fe-S] clusters.5,6 The latter are essential components of ferrochelatase and of proteins involved in the citric acid cycle and the electron transport chain. Recently, Levi et al reported the existence of ferritin in mitochondria (MtFt).7 MtFt is composed of 22-kDa ferritin subunits that display similarity to H-ferritin, possess ferroxidase activity, and assemble into multimeric ferritin shells that bind iron.7 However, although MtFt resembles H-ferritin, its function is unknown.

In this issue of Blood, Nie and colleagues examine the role of MtFt in cellular iron uptake and distribution using a cell line stably transfected to express the murine MtFt gene under control of a tetracycline-responsive promoter. They show that overexpression of MtFt results in an increase in IRP-IRE mRNA interaction, an increase in TfR1 levels, and a decrease in cytoplasmic ferritin synthesis. This constellation of findings provides direct evidence that the expression of MtFt produces a state of relative cytoplasmic iron deprivation. MtFt expression is also shown to decrease the enzymatic activities of [4Fe-4S] cluster-containing cytosolic aconitase and mitochondrial aconitase. An intriguing finding in their study is that when compared with noninduced cells, MtFt-overexpressing cells take up a greater amount of iron that is preferentially incorporated into MtFt rather than into cytoplasmic ferritin. Moreover, iron in MtFt appears to be less accessible to chelation than iron sequestered in cytoplasmic ferritin. These elegant studies help bring into focus a role for MtFt as a protein that not only sequesters iron but also modulates the trafficking of iron through the cytoplasm.

Also in this issue of Blood, Napier and colleagues provide an up-to-date review of our current understanding of iron trafficking and processing in mitochondria, illustrating how studies of genetic diseases associated with mitochondrial iron overloading have led to advances in this field. These diseases include X-linked sideroblastic anemia (caused by a defective erythroid-specific 5-aminolevulinic acid synthase), sideroblastic anemia with ataxia (caused by mutations in the ABCB7 gene that encodes a transporter for Fe-S clusters), and Friedreich ataxia (caused by a mutation in the gene for frataxin). The review includes a discussion of heme synthesis, Fe-S cluster biogenesis, MtFt, and frataxin. Building on observations made in mitochondrial iron overload disorders, the authors propose an interesting and testable model in which frataxin plays a regulatory role in the trafficking of mitochondrial iron for heme synthesis, Fe-S cluster formation, and storage in MtFt.

Clearly, mitochondrial iron metabolism is an exciting area for investigation. We look forward to future studies that will further illuminate the role this powerhouse plays in cellular iron metabolism in health and disease. ▪

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