Mitochondrial De Novo Assembly of Iron-Sulfur Clusters in Mammals: Complex Matters in a Complex That Matters

Iron-sulfur clusters (Fe-S or ISC) are essential cofactors that function in a wide range of biological pathways. In mammalian cells, Fe-S biosynthesis primarily relies on mitochondria and involves a concerted group of evolutionary-conserved proteins forming the ISC pathway. In the early stage of the ISC pathway, the Fe-S core complex is required for de novo assembly of Fe-S. In humans, the Fe-S core complex comprises the cysteine desulfurase NFS1, the scaffold protein ISCU2, frataxin (FXN), the ferredoxin FDX2, and regulatory/accessory proteins ISD11 and Acyl Carrier Protein (ACP). In recent years, the field has made significant advances in unraveling the structure of the Fe-S core complex and the mechanism underlying its function. Herein, we review the key recent findings related to the Fe-S core complex and its components. We highlight some of the unanswered questions and provide a model of the Fe-S assembly within the complex. In addition, we briefly touch on the genetic diseases associated with mutations in the Fe-S core complex components.