Role of Nfu1 and Bol3 in iron-sulfur cluster transfer to mitochondrial clients

Iron-sulfur (Fe-S) clusters are essential for many cellular processes, ranging from aerobic respiration, metabolite biosynthesis, ribosome assembly and DNA repair. Mutations in NFU1 and BOLA3 have been linked to genetic diseases with defects in mitochondrial Fe-S centers. Through genetic studies in yeast, we demonstrate that Nful functions in a late step of [4Fe-45] cluster biogenesis that is of heightened importance during oxidative metabolism. Proteomic studies revealed Nful physical interacts with components of the ISA [4Fe-45] assembly complex and client proteins that need [4Fe-45] clusters to function. Additional studies focused on the mitochondrial BolA proteins, Bol1 and Bol3 (yeast homolog to human BOLA3), revealing that Bol1 functions earlier in Fe-S biogenesis with the monothiol glutaredoxin, Grx5, and Bol3 functions late with Nful. Given these observations, we propose that Nful, assisted by Bol3, functions to facilitate Fe-S transfer from the biosynthetic apparatus to the client proteins preventing oxidative damage to [4Fe-45] clusters.