title: Protein expression profiles in patients carrying NFU1 mutations. Contribution to the pathophysiology of the disease.
abstract: Cofactor disorders of mitochondrial energy metabolism are a heterogeneous group of diseases with a wide variety of clinical symptoms, particular metabolic profiles and variable enzymatic defects. Mutations in NFU1 were recently identified in patients with fatal encephalopathy displaying a biochemical phenotype consistent with defects in lipoic acid-dependent enzymatic activities and respiratory chain complexes. This discovery highlighted the molecular function of NFU1 as an iron-sulfur(Fe-S) cluster protein necessary for lipoic acid biosynthesis and respiratory chain complexes activities. To understand the pathophysiological mechanisms underlying this disease we have characterized the protein expression profiles of patients carrying NFU1 mutations. Fibroblasts from patients with the p.Gly208Cys mutation showed complete absence of protein-bound lipoic acid and decreased SDHA and SDHB subunits of complex II. In contrast, subunits of other respiratory chain complexes were normal. Protein lipoylation was also decreased in muscle and liver but not in other tissues available (brain, kidney, lung) from NFU1 patients. Although levels of the respiratory chain subunits were unaltered in tissues, BN-PAGE showed an assembly defect for complex II in muscle, consistent with the low enzymatic activity of this complex. This study provides new insights into the molecular bases of NFU1 disease as well as into the regulation of NFU1 protein in human tissues. We demonstrate a ubiquitous expression of NFU1 protein and further suggest that defects in lipoic acid biosynthesis and complex II are the main molecular signature of this disease, particularly in patients carrying the p.Gly208Cys mutation.
authors.affiliation: Secció d'Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS, 08028 Barcelona, Spain.
authors.forename: Xènia
authors.initials: X
authors.lastname: Ferrer-Cortès
authors.forename: Aida
authors.initials: A
authors.lastname: Font
authors.forename: Núria
authors.initials: N
authors.lastname: Bujan
authors.forename: Aleix
authors.initials: A
authors.lastname: Navarro-Sastre
authors.forename: Leslie
authors.initials: L
authors.lastname: Matalonga
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Arranz
authors.forename: Encarnació
authors.initials: E
authors.lastname: Riudor
authors.forename: Mireia
authors.initials: M
authors.lastname: del Toro
authors.forename: Angels
authors.initials: A
authors.lastname: Garcia-Cazorla
authors.forename: Jaume
authors.initials: J
authors.lastname: Campistol
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D004579:Electron Transport / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D014176:Protein Biosynthesis / Q000235:genetics*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D008063:Thioctic Acid / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C426067:NFU1 protein, human; D011506:Proteins; D008063:Thioctic Acid