Human Iron−Sulfur Cluster Assembly, Cellular Iron Homeostasis, and Disease

摘要

Iron-sulfur (Fe-S) proteins contain prosthetic groups consisting of two or more iron atomsnbridged by sulfur ligands, which facilitate multiple functions, including redox activity, enzymatic function,nandmaintenance of structural integrity.More than 20 proteins are involved in the biosynthesis of iron-sulfurnclusters in eukaryotes. Defective Fe-S cluster synthesis not only affects activities of many iron-sulfurnenzymes, such as aconitase and succinate dehydrogenase, but also alters the regulation of cellular ironnhomeostasis, causing both mitochondrial iron overload and cytosolic iron deficiency. In this work, we reviewnhuman Fe-S cluster biogenesis and human diseases that are caused by defective Fe-S cluster biogenesis.nFe-S cluster biogenesis takes place essentially in every tissue of humans, and products of human diseasengenes, including frataxin, GLRX5, ISCU, and ABCB7, have important roles in the process. However, thenhuman diseases, Friedreich ataxia, glutaredoxin 5-deficient sideroblastic anemia, ISCU myopathy, andnABCB7 sideroblastic anemia/ataxia syndrome, affect specific tissues, while sparing others. Here we discussnthe phenotypes caused by mutations in these different disease genes, and we compare the underlyingnpathophysiology and discuss the possible explanations for tissue-specific pathology in these diseases causednby defective Fe-S cluster biogenesis.