IBA57 is a mitochondrial iron-sulfur (Fe-S) cluster assembly factor essential for [4Fe-4S] protein maturation in the late stage of the iron-sulfur cluster assembly pathway 1. IBA57 functions as part of a multi-protein complex; it recruits ISCA2 through a [2Fe-2S] cluster-bridged heterodimeric interaction, and this complex is resistant to oxidative environments and capable of transferring Fe-S clusters to target apoprotein substrates 2. Unlike its bacterial homolog YgfZ, mitochondrial IBA57 operates independently of tetrahydrofolate cofactors despite structural similarities to folate-binding enzymes 3. IBA57 deficiency impairs the maturation of multiple mitochondrial [4Fe-4S] proteins, including respiratory complexes I and II, aconitase, and lipoic acid synthase, while sparing [2Fe-2S] protein maturation 14. Pathogenic IBA57 variants cause autosomal recessive Multiple Mitochondrial Dysfunction Syndrome 3 (MMDS3) and Spastic Paraplegia 74, characterized by early-onset developmental delay, optic atrophy, spastic paraplegia, hyperglycinemia, cavitating leukoencephalopathy, and respiratory insufficiency 56. Mutations lead to proteolytic degradation of IBA57 protein below critical physiological levels, resulting in lethal biochemical phenotypes with severe neurological and muscular manifestations 4. Early genetic testing enables diagnosis and family screening for this rare but severe mitochondrial disorder 5.