The lysosome is an acidic multi-functional organelle with roles in macromolecular digestion, nutrient sensing, and signaling. However, why cells require acidic lysosomes to proliferate and which nutrients become limiting under lysosomal dysfunction are unclear. To address this, we performed CRISPR-Cas9-based genetic screens and identified cholesterol biosynthesis and iron uptake as essential metabolic pathways when lysosomal pH is altered. While cholesterol synthesis is only necessary, iron is both necessary and sufficient for cell proliferation under lysosomal dysfunction. Remarkably, iron supplementation restores cell proliferation under both pharmacologic and genetic-mediated lysosomal dysfunction. The rescue was independent of metabolic or signaling changes classically associated with increased lysosomal pH, uncoupling lysosomal function from cell proliferation. Finally, our experiments revealed that lysosomal dysfunction dramatically alters mitochondrial metabolism and hypoxia inducible factor (HIF) signaling due to iron depletion. Altogether, these findings identify iron homeostasis as the key function of lysosomal acidity for cell proliferation.

中文翻译：

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维持铁稳态是溶酶体酸度对细胞增殖的关键作用。

溶酶体是一种酸性多功能细胞器，在大分子消化，营养物感应和信号传导中起作用。然而，为什么细胞需要酸性溶酶体来增殖以及在溶酶体功能障碍下哪些营养物质变得有限。为了解决这个问题，我们进行了基于CRISPR-Cas9的遗传筛选，并确定了溶酶体pH值改变时胆固醇的生物合成和铁吸收是必需的代谢途径。虽然仅胆固醇合成是必需的，但铁是溶酶体功能障碍下细胞增殖所必需的和充分的。值得注意的是，在药理作用和遗传介导的溶酶体功能障碍下，补铁可恢复细胞增殖。抢救独立于代谢或信号变化（通常与溶酶体pH值升高相关），溶酶体功能与细胞增殖脱钩。最后，我们的实验表明，溶酶体功能异常会由于铁耗竭而极大地改变线粒体代谢和缺氧诱导因子（HIF）信号。总而言之，这些发现将铁稳态作为溶酶体酸度对细胞增殖的关键功能。