Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation

Brain. 2024 Jan 18:awae018. doi: 10.1093/brain/awae018. Online ahead of print.


Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, nor were the effects on cell membranes or the wider cell known. Using patient-derived cells we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases. Lysosomes are also more numerous in Drosophila neural progenitor cells expressing mutant Atad3, which exhibit abundant membrane-bound cholesterol aggregates, many of which co-localize with lysosomes. Using nutrient restriction and cholesterol supplementation, we show that the Drosophila Atad3 mutant displays heightened cholesterol dependence. Collectively, these findings suggest elevated cholesterol enhances tolerance to pathological ATAD3 variants, at a cost of inducing cholesterol aggregation in membranes, which lysosomal clearance only partly mitigates.

PMID:38242545 | DOI:10.1093/brain/awae018