ISCU

ISCU stands for iron-sulfur cluster assembly protein. It is a highly conserved component of the cellular machinery that builds iron-sulfur (Fe-S) clusters, essential cofactors for a wide range of enzymes involved in respiration, metabolism, DNA repair, and other fundamental processes. ISCU is found across bacteria, archaea, and eukaryotes, reflecting the ancient and universal importance of Fe-S biogenesis.

In the Fe-S cluster assembly pathway, ISCU serves as a scaffold protein that temporarily binds iron and sulfur to form nascent Fe-S clusters. In mitochondria this process proceeds with the help of cysteine desulfurases such as NFS1 and associated partners, transferring sulfur to ISCU and enabling cluster assembly which is then transferred to recipient apoproteins or routed to the cytosolic iron-sulfur protein assembly system. In bacteria, a homologous IscU plays a parallel role, working with IscS (a cysteine desulfurase) and chaperones to assemble and deliver clusters to target proteins.

ISCU is a small, primarily mitochondrial protein in many organisms, and in humans the ISCU gene produces multiple isoforms through alternative splicing that localize to the mitochondrial matrix where Fe-S assembly occurs. The protein contains conserved cysteine residues that coordinate the iron-sulfur cluster during assembly.

Mutations or reduced expression of ISCU are linked to human disease, most notably mitochondrial myopathy with exercise intolerance. A common ISCU-related defect involves mis-splicing or regulation that lowers ISCU protein levels in skeletal muscle, impairing Fe-S cluster formation and mitochondrial function. ISCU thus plays a central role in cellular energy metabolism and the maturation of numerous Fe-S-dependent enzymes.