NFU1 is a mitochondrial iron-sulfur cluster scaffold protein that assembles [4Fe-4S] clusters and delivers them to target proteins 1. Mechanistically, NFU1 functions as a key component in late-stage [4Fe-4S] cluster maturation, where ISCA1 orchestrates the coordinated interaction between ISCA2 and NFU1 to facilitate cluster transfer from the ISCA1-ISCA2 assembly complex to recipient apo proteins 2. The structural plasticity of NFU1's N- and C-terminal domains is crucial for protein partner recognition and modulating cluster trafficking 3. NFU1 mutations cause Multiple Mitochondrial Dysfunction Syndrome 1 (MMDS1) and spastic paraplegia 93, characterized by severe mitochondrial respiratory chain defects, impaired complex II and pyruvate dehydrogenase activity, and reduced lipoic acid biosynthesis 145. Clinically, NFU1 deficiency leads to mitochondrial encephalomyopathies, early-life death, and pulmonary arterial hypertension with ~70% penetrance in patients with the G208C mutation 67. Disease mechanisms include elevated mtDNA mutability and oxidative stress 4. Lipoic acid supplementation alleviates mitochondrial dysfunction and angiogenic deficiency in NFU1-deficient models, suggesting therapeutic potential 7.