A novel fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins

Iron-sulfur cluster (ISC) biogenesis is a complex process involving at least 25 components in mitochondria and cytosol. The function of the mitochondrial ISC assembly protein NFU1 is unknown, the more so as its depletion in yeast is not associated with a conspicuous phenotype. Here, we identified a homozygous point mutation in NFU1 of nine patients with fatal infantile encephalopathy. Altered plasma amino acid and urinary organic acid profiles and decreased activities of pyruvate dehydrogenase and glycine cleavage system suggested a defect in lipoic acid synthesis. Disorders in lipoic acid biogenesis have not been reported before. Depletion of NFU1 by RNA interference in human cell culture caused a specific defect of the mitochondrial Fe S proteins lipoic acid synthase and succinate dehydrogenase but not of other Fe-S proteins. In comparison, depletion of the Fe-S scaffold protein ISCU severely affected all tested Fe-S proteins. We conclude that NFU1 functions as a specificity factor for maturation of a subset of Fe-S proteins.