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Weber, Ross A.; Yen, Frederick S.; Nicholson, Shirony P.V.; Alwaseem, Hanan; Bayraktar, Erol C.; Alam, Mohammad; Timson, Rebecca C.; La, Konnor; Abu-Remaileh, Monther; Molina, Henrik; Birsoy, Kıvanç
Molecular cell, 02/2020, Volume: 77, Issue: 3Journal Article
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. Display omitted •Cells starve for cholesterol and iron under lysosomal dysfunction•Upon increased lysosomal pH, only iron addition enables cell proliferation•Iron does not restore lysosomal pH-related catabolic and signaling functions•Iron reverses other cellular processes related to depleted cellular iron The lysosome is a multi-functional organelle whose low pH is required for cell viability. Weber et al. identified iron as necessary and sufficient for cell proliferation under lysosomal dysfunction. While iron addition uncouples lysosomal acidity from cell viability, iron chelation combined with lysosome-targeting compounds represents a potential cancer therapeutic strategy.
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