Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis.
Iron-sulfur (Fe-S) clusters are required for the functions of mitochondrial aconitase, mammalian iron regulatory protein 1, and many other proteins in multiple subcellular compartments. Recent studies in Saccharomyces cerevisiae indicated that Fe-S cluster biogenesis also has an important role in mitochondrial iron homeostasis. Here we report the functional analysis of the mitochondrial and cytosolic isoforms of the human Fe-S cluster scaffold protein, ISCU. Suppression of human ISCU by RNAi not only inactivated mitochondrial and cytosolic aconitases in a compartment-specific manner but also inappropriately activated the iron regulatory proteins and disrupted intracellular iron homeostasis. Furthermore, endogenous ISCU levels were suppressed by iron deprivation. These results provide evidence for a coordinated response to iron deficiency that includes activation of iron uptake, redistribution of intracellular iron, and decreased utilization of iron in Fe-S proteins.
Tong
Wing-Hang
WH
National Institute of Child Health and Human Development, Cell Biology and Metabolism Branch, Bethesda, Maryland 20892, USA.
Rouault
Tracey A
TA
D000154:Aconitate Hydratase / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020218:Response Elements
C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D007501:Iron; D000154:Aconitate Hydratase; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2