Mechanism of mitochondrial [2Fe-2S] cluster biosynthesis

Iron‑sulfur (Fe-S) clusters constitute ancient cofactors that accompany a versatile range of fundamental biological reactions across eukaryotes and prokaryotes. Several cellular pathways exist to coordinate iron acquisition and sulfur mobilization towards a scaffold protein during the tightly regulated synthesis of Fe-S clusters. The mechanism of mitochondrial eukaryotic [2Fe-2S] cluster synthesis is coordinated by the Iron-Sulfur Cluster (ISC) machinery and its aberrations herein have strong implications to the field of disease and medicine which is therefore of particular interest. Here, we describe our current knowledge on the step-by-step mechanism leading to the production of mitochondrial [2Fe-2S] clusters while highlighting the recent developments in the field alongside the challenges that are yet to be overcome. •In mitochondria, [2Fe-2S] clusters are assembled on the scaffold protein ISCU.•ISCU assembles [2Fe-2S] cluster sequentially with iron coming first followed by sulfur.•Sulfur is provided as a persulfide and its supply is regulated by the frataxin protein.•Ferredoxin-2 cleaves the persulfide on ISCU into sulfide.•ISCU dimerization is likely needed in the final step generating [2Fe-2S] clusters.