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Mitochondrial dysfunction associated with a mutation in the Notch3 gene in a CADASIL family
P de la Peña1, B Bornstein, P del Hoyo
1Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
Insights
Mitochondrial dysfunction, potentially linked to Notch3 gene mutations in Cerebral Autosomal Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), may involve defects in oxidative phosphorylation.
Area of Science:
- Neurogenetics
- Mitochondrial Biology
- Cellular Pathophysiology
Background:
- Cerebral Autosomal Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic disorder causing strokes and dementia, linked to Notch3 gene mutations.
- Notch signaling is crucial for development in organisms like Drosophila melanogaster.
Purpose of the Study:
- To investigate potential mitochondrial dysfunction in CADASIL patients with Notch3 gene mutations.
- To explore the role of Notch signaling in mitochondrial function.
Main Methods:
- Biochemical, histochemical, molecular, and genetic analyses were conducted on patient muscle and fibroblast samples.
- Drosophila melanogaster N(55e11) mutant was used for complementary biochemical and molecular studies.
Main Results:
- Patients showed decreased activity in mitochondrial Complex I (NADH dehydrogenase) and Complex V (ATP synthase).
- One patient exhibited ragged-red fibers and abnormal cytochrome c oxidase staining in muscle biopsies.
- The Drosophila N(55e11) mutation reduced the activity of mitochondrial respiratory complexes I and V.
Conclusions:
- Mitochondrial respiratory chain activity is influenced by the Notch signaling pathway.
- Mitochondrial dysfunction might be a key factor in CADASIL pathophysiology, potentially involving oxidative phosphorylation defects.
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.