Maintaining Iron Homeostasis Is the Key Role of Lysosomal Acidity for Cell Proliferation
Open accessAbstract
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.
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- Authors
- Weber, R. A., Yen, F. S., Nicholson, S. P. V., Alwaseem, H., Bayraktar, E. C., Alam, M., Timson, R. C., La, K., Abu-Remaileh, M., Molina, H., & Birsoy, K.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Rockefeller University (US)
- Medical University of Graz (AT)
- Stanford University (US)
- Corresponding author
- Birsoy, Kıvanç
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 77
- Issue
- 3
- Pages
- 645-655.e7
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC7176020
- OpenAlex
- W3001952391
- Cited by
- 236
- References
- 46
- Citations by year
- 2026: 34 · 2025: 40 · 2024: 34 · 2023: 32 · 2022: 37 · 2021: 33 · 2020: 25
- FWCI
- 23.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- March of Dimes Foundation
- Searle Scholars Program
- Leona M. and Harry B. Helmsley Charitable Trust
- Pew Charitable Trusts
- American Association for Cancer Research
- National Institute of General Medical Sciences
- Irma T. Hirschl Trust
- National Institutes of Health
- Sidney Kimmel Foundation
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- lysosomal pH, lysosomal dysfunction, iron homeostasis, cell proliferation, cholesterol biosynthesis, iron absorption, iron supplementation, mitochondrial metabolism, hypoxia-inducible factor signaling
- MeSH terms
- Cholesterol, HeLa Cells, Homeostasis, Humans, Hydrogen-Ion Concentration, Iron, Lysosomes, Mitochondria, Signal Transduction, Jurkat Cells, Cell Proliferation, HEK293 Cells
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