title: A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins.
abstract: We report on ten individuals with a fatal infantile encephalopathy and/or pulmonary hypertension, leading to death before the age of 15 months. Hyperglycinemia and lactic acidosis were common findings. Glycine cleavage system and pyruvate dehydrogenase complex (PDHC) activities were low. Homozygosity mapping revealed a perfectly overlapping homozygous region of 1.24 Mb corresponding to chromosome 2 and led to the identification of a homozygous missense mutation (c.622G > T) in NFU1, which encodes a conserved protein suggested to participate in Fe-S cluster biogenesis. Nine individuals were homozygous for this mutation, whereas one was compound heterozygous for this and a splice-site (c.545 + 5G > A) mutation. The biochemical phenotype suggested an impaired activity of the Fe-S enzyme lipoic acid synthase (LAS). Direct measurement of protein-bound lipoic acid in individual tissues indeed showed marked decreases. Upon depletion of NFU1 by RNA interference in human cell culture, LAS and, in turn, PDHC activities were largely diminished. In addition, the amount of succinate dehydrogenase, but no other Fe-S proteins, was decreased. In contrast, depletion of the general Fe-S scaffold protein ISCU severely affected assembly of all tested Fe-S proteins, suggesting that NFU1 performs a specific function in mitochondrial Fe-S cluster maturation. Similar biochemical effects were observed in Saccharomyces cerevisiae upon deletion of NFU1, resulting in lower lipoylation and SDH activity. Importantly, yeast Nfu1 protein carrying the individuals' missense mutation was functionally impaired. We conclude that NFU1 functions as a late-acting maturation factor for a subset of mitochondrial Fe-S proteins.
authors.affiliation: Division of Inborn Errors of Metabolism, Department of Biochemistry and Molecular Genetics, Hospital Clinic, Instituto de Investigación Biomédica Pi Sunyer, 08028 Barcelona, Spain.
authors.forename: Aleix
authors.initials: A
authors.lastname: Navarro-Sastre
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
authors.forename: Oliver
authors.initials: O
authors.lastname: Stehling
authors.forename: Marta A
authors.initials: MA
authors.lastname: Uzarska
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Arranz
authors.forename: Mireia
authors.initials: M
authors.lastname: Del Toro
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Labayru
authors.forename: Joseba
authors.initials: J
authors.lastname: Landa
authors.forename: Aida
authors.initials: A
authors.lastname: Font
authors.forename: Judit
authors.initials: J
authors.lastname: Garcia-Villoria
authors.forename: Begoña
authors.initials: B
authors.lastname: Merinero
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
authors.forename: Luis Gonzalez
authors.initials: LG
authors.lastname: Gutierrez-Solana
authors.forename: Jaume
authors.initials: J
authors.lastname: Campistol
authors.forename: Angels
authors.initials: A
authors.lastname: Garcia-Cazorla
authors.forename: Julian
authors.initials: J
authors.lastname: Vaquerizo
authors.forename: Encarnació
authors.initials: E
authors.lastname: Riudor
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.forename: Roland
authors.initials: R
authors.lastname: Lill
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005260:Female; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007223:Infant; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D020125:Mutation, Missense; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013466:Sulfurtransferases / Q000378:metabolism; D008063:Thioctic Acid / Q000378:metabolism; D014166:Transferases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; C121524:NFU1 protein, S cerevisiae; C426067:NFU1 protein, human; D029701:Saccharomyces cerevisiae Proteins; C064525:glycine cleavage system; D008063:Thioctic Acid; D013385:Succinate Dehydrogenase; D000594:Amino Acid Oxidoreductases; D014166:Transferases; D013466:Sulfurtransferases; C116435:lipoic acid synthase
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