IRP1 is an iron-sulfur protein related to mitochondrial aconitase, a citric acid cycle enzyme, and it functions as a cytosolic aconitase in cells that are iron replete. Regulation of RNA binding activity of IRP1 involves a transition from a form of IRP1 in which a 4Fe-4S cluster is bound, to a form that loses both iron and aconitase activity. The 4Fe-4S containing protein does not bind IREs. Controlled degradation of the iron-sulfur cluster and mutagenesis reveals that the physiologically relevant form of the RNA binding protein in iron-depleted cells is apoprotein. The status of the cluster appears to determine whether IRP1 will bind RNA. Over the past decade, we have identified mammalian enzymes of iron-sulfur cluster assembly that are homologous to the NifS, ISCU and Nif U, ferredoxin and ferredoxin reductase genes implicated in bacterial iron-sulfur cluster assembly, and we have shown that these gene products facilitate assembly of the iron- sulfur cluster of IRP1. We have discovered that frataxin transcription is iron-dependently regulated and frataxin expression decreases when there is cytosolic iron deficiency in wild-type and in fibroblasts and lymphoblasts from Friedreich ataxia patients. We discovered that a mutation in the scaffold protein, ISCU, causes a rare myopathy. In both Friedreich ataxia and ISCU myopathy, our data indicate that mitochondrial iron overload occurs in conjunction with cytosolic iron depletion. In collaboration, we discovered that NFU1 and BOLA3 mutations cause a human disease characterized by lactic acidosis and lipoic acid deficiency. We predicted that other rare genetic diseases characterized by mitochondrial compromise were caused by mutations in the genes responsible for iron-sulfur cluster biogenesis, and we collaborated to discover that mutations of NFS1 cause neonatal mitochondrial disease. We are characterizing the steps that chaperone transfer of nascent iron-sulfur clusters from their association with the initial assembly apparatus to proteins that require iron-sulfur clusters for function. We have extensively studied the metabolic remodeling of skeletal muscle metabolism in ISCU myopathy and discovered several compensatory pathways that help to maintain energy homeostasis. We have also discovered multiple reasons that limit the phenotype of ISU myopathy to skeletal muscles, while largely sparing other tissues. We are developing antisense treatment therapy for ISCU myopathy, and we recently demonstrated that FGF21 is a good biomarker for muscle disease in ISCU myopathy. We are also actively working to discover how SDHB acquires its three Fe-S clusters.

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Maio, Nunziata; Ghezzi, Daniele; Verrigni, Daniela et al. (2016) Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB. Cell Metab 23:292-302
Saxena, Neetu; Maio, Nunziata; Crooks, Daniel R et al. (2016) SDHB-Deficient Cancers: The Role of Mutations That Impair Iron Sulfur Cluster Delivery. J Natl Cancer Inst 108:
Maio, N; Rouault, T A (2016) Mammalian Fe-S proteins: definition of a consensus motif recognized by the co-chaperone HSC20. Metallomics 8:1032-1046
Rouault, Tracey A (2015) Iron-sulfur proteins hiding in plain sight. Nat Chem Biol 11:442-5
Maio, Nunziata; Rouault, Tracey A (2015) Iron-sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery. Biochim Biophys Acta 1853:1493-512
Rouault, Tracey A (2015) Mammalian iron-sulphur proteins: novel insights into biogenesis and function. Nat Rev Mol Cell Biol 16:45-55
Maio, Nunziata; Singh, Anamika; Uhrigshardt, Helge et al. (2014) Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster delivery. Cell Metab 19:445-57
Crooks, Daniel R; Natarajan, Thanemozhi G; Jeong, Suh Young et al. (2014) Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle. Hum Mol Genet 23:24-39
Holmes-Hampton, Gregory P; Tong, Wing-Hang; Rouault, Tracey A (2014) Biochemical and biophysical methods for studying mitochondrial iron metabolism. Methods Enzymol 547:275-307
Lim, Sze Chern; Friemel, Martin; Marum, Justine E et al. (2013) Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes. Hum Mol Genet 22:4460-73

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