Regulation of Intracellular Iron Metabolism
Our overall goal is to understand how iron metabolism is regulated in mammals and in patients with rare diseases, ranging from familial renal cancers, to anemias and polycythemias, and to brain and muscle disorders. In cells, iron regulatory proteins 1 and 2 (IRP1 and IRP2) regulate expression of numerous proteins of iron metabolism. In cells that are iron-depleted, these proteins bind to RNA stem-loops in transcripts known as iron-responsive elements (IREs). IRP binding stabilizes the mRNA that encodes transferrin receptor, and represses translation of transcripts that contain IREs near the 5' end such as ferritin H and L chains. IRP1 is an iron-sulfur protein that functions as an aconitase in iron-replete cells. IRP2 is homologous to IRP1, but it undergoes iron-dependent degradation in iron-replete cells. In mouse models, loss of IRP2 results in mild anemia, erythropoietic protoporphyria, and adult-onset neurodegeneration. These phenotypes are likely the result of functional iron deficiency within neurons and red cell precursors. We are studying the molecular mechanisms that lead to various rare disease phenotypes, and we have developed pre-clinical treatments for the neurodegeneration of Irp2-/- mice, an antisense RNA treatment for ISCU myopathy, bone marrow transplant treatment for patients with heme oxygenase deficiency, and new treatments for renal cancer in patients with hereditary leiomyomatosis and kidney cancer.
Mammalian iron-sulfur cluster biogenesis
The goals of studying mammalian iron-sulfur biogenesis are to understand how iron-sulfur prosthetic groups are assembled and delivered to target proteins in the various compartments of mammalian cells, including mitochondria, cytosol, and nucleus. In addition, we seek to understand the role of iron-sulfur cluster assembly in regulation of mitochondrial iron homeostasis, and to understand the pathogenesis of diseases such as Friedreich ataxia, ISCU myopathy, sideroblastic anemia, and numerous types of neonatal acidosis in which mitochondrial iron cluster biogenesis is impaired.We have identified mammalian homologues of over twenty proteins involved in bacterial and yeast iron-sulfur cluster biogenesis. There are now ten human disease genes that impair iron sulfur cluster biogenesis, including ISCU, frataxin, and glutaredoxin 5, LYRM4, NFU1, BOLA3, and a key feature of each disease is that mitochondrial dysfunction occurs in particular tissues and is followed by mitochondrial iron overload. Using cell lines and tissue from patients, we are working to understand how mitochondrial iron homeostasis is regulated. We recently discovered an important key to how nascent iron-sulfur clusters are targeted to recipient proteins by the chaperone-cochaperone complex composed of HSPA9, HSC20, the scaffold ISCU bearing a newly formed iron-sulfur cluster, and recipient proteins, which contain LYR motifs to which HSC20 binds. LYR motifs, and iterations of the motif, are found in numerous mitochondrial and cytosolic/nuclear proteins, some of which have not yet been shown to contain iron-sulfur clusters. However, the distribution of these motifs suggests that the motifs are often functional, and many more iron-sulfur proteins are present in mammalian cells than is presently recognized. Through informatics, we are discovering entire classes of iron-sulfur proteins in mammalian cells. Our discoveries may have broad impact on how mammalian biochemistry is performed and interpreted by significantly increasing the number of known iron-sulfur proteins, which must be protected from oxygen in experiments.