Cytosolic Fe/S protein biogenesis: a crossroads of Fe/S cluster machineries

Iron-sulfur (Fe/S) clusters are essential inorganic cofactors required for nearly all organisms. These cofactors do not spontaneously form in cells or on proteins; they require at least one of six dedicated Fe/S protein biogenesis pathways. The eukaryotic cytosol is an intriguing cellular compartment for Fe/S protein biogenesis because genetic evidence across the eukaryotic supergroups suggests the unique occurrence of multiple, interconnected pathways being capable of fulfilling the quota of Fe/S clusters in the cytosol and nucleus. The reliance of multiple pathways for cytosolic and nuclear Fe/S protein biogenesis was first established by genetic studies in the yeast, human, and plant model organisms, which demonstrated the essentiality of mitochondrial Fe/S protein biogenesis in supplying an exported substrate to the cytosol. With the great expansion of genomic data, we have learned that other organisms have replaced the essential mitochondrial system with other Fe/S biogenesis proteins stemming from prokaryotes. Studies have demonstrated that the rewiring of cytosolic Fe/S protein biogenesis can also facilitate the reductive evolution of mitochondria and even lead to complete loss of the organelle in some organisms. This review provides an updated overview of how these differing Fe/S protein biogenesis pathways intersect and the corresponding mechanistic considerations.