Mitochondrial dysfunction associated with a mutation in the Notch3 gene ina CADASIL family

Background: Cerebral autosomal arteriopathy with subcortical infarcts and l eukoencephalopathy (CADASIL) is characterized by recurrent subcortical isch emic strokes and dementia caused by mutations in the Notch3 gene. In Drosop hila melanogaster, Notch signaling has a pleiotropic effect, affecting most tissues of the organism during development. Objective: To characterize a p otential 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 pat ients of a Spanish family with CADASIL. Additional biochemical and molecula r analyses of the N-55e11 mutant of D. melanogaster were performed. Results : In muscle biopsy specimens, a significant decrease was found in the activ ity of complex I (NADH [reduced form of nicotinamide adenine dinucleotide] dehydrogenase), and in one patient, histochemical analysis showed the prese nce of ragged-red fibers with abnormal cytochrome c oxidase staining. Reduc ed fibroblast activity of complex V (ATP synthase) was found. Supporting da ta on patients with CADASIL, it was found that the mutation N-55e11 in Dros ophila 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 i n patients with CADASIL may be an epiphenomenon, but results of this study suggest that the pathophysiology of the disease could include a defect in o xidative phosphorylation.