title: Mitochondrial dysfunction associated with a mutation in the Notch3 gene in a CADASIL family.
abstract: BACKGROUND
  Cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by recurrent subcortical ischemic strokes and dementia caused by mutations in the Notch3 gene. In Drosophila melanogaster, Notch signaling has a pleiotropic effect, affecting most tissues of the organism during development.
  
  
  OBJECTIVE
  To characterize a potential mitochondrial dysfunction associated with mutations in the Notch3 gene.
  
  
  METHODS
  Biochemical, histochemical, molecular, and genetic analyses were performed on muscle biopsy specimens and fibroblasts obtained from patients of a Spanish family with CADASIL. Additional biochemical and molecular analyses of the N(55e11) mutant of D. melanogaster were performed.
  
  
  RESULTS
  In muscle biopsy specimens, a significant decrease was found in the activity of complex I (NADH [reduced form of nicotinamide adenine dinucleotide] dehydrogenase), and in one patient, histochemical analysis showed the presence of ragged-red fibers with abnormal cytochrome c oxidase staining. Reduced fibroblast activity of complex V (ATP synthase) was found. Supporting data on patients with CADASIL, it was found that the mutation N(55e11) in Drosophila decreases the activity of mitochondrial respiratory complexes I and V.
  
  
  CONCLUSIONS
  Mitochondrial respiratory chain activity responds, directly or indirectly, to the Notch signaling pathway. Mitochondrial dysfunction in patients with CADASIL may be an epiphenomenon, but results of this study suggest that the pathophysiology of the disease could include a defect in oxidative phosphorylation.
authors.affiliation: Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: de la Peña
authors.forename: B
authors.initials: B
authors.lastname: Bornstein
authors.forename: P
authors.initials: P
authors.lastname: del Hoyo
authors.forename: M A
authors.initials: MA
authors.lastname: Fernández-Moreno
authors.forename: M A
authors.initials: MA
authors.lastname: Martín
authors.forename: Y
authors.initials: Y
authors.lastname: Campos
authors.forename: C
authors.initials: C
authors.lastname: Gómez-Escalonilla
authors.forename: J A
authors.initials: JA
authors.lastname: Molina
authors.forename: A
authors.initials: A
authors.lastname: Cabello
authors.forename: J
authors.initials: J
authors.lastname: Arenas
authors.forename: R
authors.initials: R
authors.lastname: Garesse
mesh_terms: D000328:Adult; D000368:Aged; D015161:Dementia, Multi-Infarct / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004579:Electron Transport / Q000235:genetics; D042967:Electron Transport Complex I; D003576:Electron Transport Complex IV / Q000032:analysis; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D013385:Succinate Dehydrogenase; D009247:NADH, NADPH Oxidoreductases; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I