Mitochondrial dysfunction in fibroblasts derived from patients with Niemann-Pick type C disease.

Mutations in the NPC1 or NPC2 genes lead to Niemann-Pick type C (NPC) disease, a rare lysosomal storage disorder characterized by progressive neurodegeneration. These mutations result in cholesterol and glycosphingolipid accumulation in the late endosomal/lysosomal compartment. Complications in the storage of cholesterol in NPC1 mutant cells are associated with other anomalies, such as altered distribution of intracellular organelles and properties of the plasma membrane. The pathomechanism of NPC disease is largely unknown. Interestingly, other storage diseases such as Gaucher and Farber diseases are accompanied by severe mitochondrial dysfunction. This prompted us to investigate the effect of absence or dysfunction of the NPC1 protein on mitochondrial properties to confirm or deny a putative relationship between NPC1 mutations and mitochondrial function. This study was performed on primary skin fibroblasts derived from skin biopsies of two NPC patients, carrying mutations in the NPC1 gene. We observed altered organization of mitochondria in NPC1 mutant cells, significant enrichment in mitochondrial cholesterol content, increased respiration, altered composition of the respiratory chain complex, and substantial reduction in cellular ATP level. Thus, a primary lysosomal defect in NPC1 mutant fibroblasts is accompanied by deregulation of the organization and function of the mitochondrial network.