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.

中文翻译：

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ATAD3突变体中胆固醇升高是一种导致膜胆固醇聚集的补偿机制

异常的胆固醇代谢会导致神经系统疾病和神经变性，通过对 ATAD3 基因簇病理突变的研究，线粒体与胆固醇稳态紊乱有关。然而，胆固醇的变化是否是补偿性的或促成该疾病尚不清楚，对细胞膜或更广泛的细胞的影响也不清楚。使用患者来源的细胞，我们发现胆固醇扰动是病理性 ATAD3 变异的保守特征，伴随着溶酶体群体的扩大，其中含有溶酶体贮积病特征的膜螺纹。表达突变 Atad3 的果蝇神经祖细胞中的溶酶体数量也更多，这些细胞表现出丰富的膜结合胆固醇聚集体，其中许多与溶酶体共定位。通过营养限制和胆固醇补充，我们发现果蝇 Atad3 突变体表现出高度的胆固醇依赖性。总的来说，这些发现表明胆固醇升高会增强对病理性 ATAD3 变异的耐受性，但代价是诱导膜中胆固醇聚集，而溶酶体清除只能部分缓解这种聚集。