Journal of Inherited Metabolic Disease

, Volume 36, Issue 5, pp 841–847

Protein expression profiles in patients carrying NFU1 mutations. Contribution to the pathophysiology of the disease

Authors

  • Xènia Ferrer-Cortès
    • Secció d’Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS
  • Aida Font
    • Secció d’Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS
  • Núria Bujan
    • Secció d’Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS
  • Aleix Navarro-Sastre
    • Secció d’Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS
    • CIBER de Enfermedades Raras (CIBERER)
  • Leslie Matalonga
    • Secció d’Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS
  • José Antonio Arranz
    • Laboratori de Metabolopaties, Hospital Valld’Hebrón, BarcelonaUniversitat Autònoma de Barcelona
  • Encarnació Riudor
    • Laboratori de Metabolopaties, Hospital Valld’Hebrón, BarcelonaUniversitat Autònoma de Barcelona
  • Mireia del Toro
    • Servei de Neurología Pediátrica, Hospital Valld’Hebrón, BarcelonaUniversitat Autònoma de Barcelona
  • Angels Garcia-Cazorla
    • CIBER de Enfermedades Raras (CIBERER)
    • Servei de Neurología, Hospital Sant Joan de Déu
  • Jaume Campistol
    • CIBER de Enfermedades Raras (CIBERER)
    • Servei de Neurología, Hospital Sant Joan de Déu
  • Paz Briones
    • Secció d’Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS
    • CIBER de Enfermedades Raras (CIBERER)
    • Consejo Superior de Investigaciones Científicas (CSIC)
    • Secció d’Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS
    • CIBER de Enfermedades Raras (CIBERER)
    • Secció d’Errors Congènits del Metabolisme -IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic
    • Secció d’Errors Congènits del Metabolisme, Servei de Bioquímica i Genètica Molecular, Hospital Clinic, IDIBAPS
    • CIBER de Enfermedades Raras (CIBERER)
    • Secció d’Errors Congènits del Metabolisme -IBC, Servei de Bioquímica i Genètica Molecular, Hospital Clínic
Original Article

DOI: 10.1007/s10545-012-9565-z

Cite this article as:
Ferrer-Cortès, X., Font, A., Bujan, N. et al. J Inherit Metab Dis (2013) 36: 841. doi:10.1007/s10545-012-9565-z

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.

Supplementary material

10545_2012_9565_MOESM1_ESM.doc (48 kb)
Supplementary Fig. 1 Protein expression analysis in tissues of patients carrying NFU1 mutations and control individuals. (a) Expression of lipoic acid (LA) bound to PDH and KGDH E2 subunits and respiratory chain complexes subunits in NFU1 patients and control tissues from brain, kidney and lung. NDUFA9 (complex I), SDHA and SDHB (complex II), UQCRC2 and UQCRFS1 (complex III) and ATP5A (complex V). GAPDH was used as a loading control. (DOC 48 kb)

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2012