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Deletions in the ATAD3 gene cluster cause cerebellar developmental defects with mitochondrial DNA abnormalities owing to local cholesterol insufficiency

ABSTRACT: The DNA in mitochondria is associated with the inner of two membranes and it co-fractionates with the limited amount of cholesterol in the organelles. However, the effects of mitochondrial cholesterol deficiency are largely unknown, and mitochondrial disorders relating to this area of cell metabolism have not been reported hitherto. Using detailed SNP array analysis we have identified patients with impaired cerebellar development and neurological dysfunction who have large deletions in the locus encoding the ATAD3A, ATAD3B and ATAD3C genes. Patient cells with inherited ATAD3 defects display aberrant mitochondrial DNA organization and synthesis associated with disrupted cholesterol metabolism. Moreover drug-induced perturbations of cholesterol metabolism cause mitochondrial DNA disorganization in control cells. The interdependence of mitochondria and cholesterol homeostasis is further corroborated by the presence of mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann Pick type C disease. Thus, we conclude, mitochondria are fully integrated in the circuitry of cellular cholesterol homeostasis, in which ATAD3 plays a critical role, and the dual problem of perturbed cholesterol homeostasis and mitochndrila dysfunction may be widespread in neurological and neurodegenerative diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86550 | GEO | 2017/06/23

SECONDARY ACCESSION(S): PRJNA342177

REPOSITORIES: GEO

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Deletions in the ATAD3 gene cluster cause cerebellar developmental defects with mitochondrial DNA abnormalities owing to local cholesterol insufficiency

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