Uncovering the role of NFS1 in Fe-S cluster biogenesis and in the development of Infantile mitochondrial complex II/III deficiency (IMC23D) disease progression and 2. Screening single domain antibody (VHH) against a membrane transporter

Abstract

The mitochondrion is a double membrane-bound organelle found in all eukaryotic organisms. Mitochondria are endosymbiotic, autogenous organelles referred to as “Powerhouse” of cells due to their ability to synthesize ATP from oxidative phosphorylation. The number of mitochondria varies from cell to cell in an organism, depending on the function of the cells. For example, liver and muscle cells are rich in mitochondria, on the other hand, RBC cells are devoid of mitochondria. In healthy cells, mitochondrial homeostasis is mainly due to Biogenesis (fission and fusion), maintenance (recycling) and clearance. Mitochondria also act as a molecular sink to regulate the activities of many proteins. In Eukaryotes mitochondria are the major hub for the synthesis of Fe-S clusters. The Fe-S cluster biogenesis process is essentially constituted of two major events; first, the assembly of Fe-S clusters on a scaffold protein. Second, the transfer of the assembled Fe-S clusters to a recipient apo-protein. In Eukaryotic mitochondria, the sulfur transfer was accomplished by cysteine desulfurase protein NFS1, which was stabilized by ISD11 protein. ISD11 protein exclusively presents only in the eukaryotic system and absent in bacteria. On the other hand, the iron-binding protein frataxin donates Iron. The electrons required for the process of Fe-S cluster biogenesis was provided by ferredoxin reductase and ferredoxin 2. A highly conserved matrix protein ISCU acts as the scaffold where the assembly of Fe-S cluster occurs. The transfer of Fe-S cluster process is mediated by chaperone machinery comprising the mtHsp70 namely HSPA9, the J-protein cochaperone, HSCB along GLRX5. However, transfer of Fe-S clusters to apoprotein was not clearly understood. Dysfunction of Mitochondrial proteins involved in Fe-S cluster biogenesis and transfer leads to a pathological condition in humans. For example, deficiency or loss of function of scaffold protein ISCU, iron donor protein frataxin, sulfur donor protein NFS1, sulfur transfer assisting protein, ISD11 and electron transfer protein FDX2 results in mitochondrial disorders ISCU myopathy, Friedreich’s ataxia, Infantile Mitochondrial Complex II/III Deficiency (IMC23D), Combined Oxidative Phosphorylation Deficiency19 (COXPD19) and FDX2 myopathy respectively.