Abstract
Every cell must satisfy basic requirements for nutrient sensing, utilization and recycling through macromolecular breakdown to coordinate programmes for growth, repair and stress adaptation. The lysosome orchestrates these key functions through the synchronised interplay between hydrolytic enzymes, nutrient transporters and signalling factors, which together enable metabolic coordination with other organelles and regulation of specific gene expression programmes. In this Review, we discuss recent findings on lysosome-dependent signalling pathways, focusing on how the lysosome senses nutrient availability through its physical and functional association with mechanistic target of rapamycin complex 1 (mTORC1) and how, in response, the microphthalmia/transcription factor E (MiT/TFE) transcription factors exert feedback regulation on lysosome biogenesis. We also highlight the emerging interactions of lysosomes with other organelles, which contribute to cellular homeostasis. Lastly, we discuss how lysosome dysfunction contributes to diverse disease pathologies and how inherited mutations that compromise lysosomal hydrolysis, transport or signalling components lead to multi-organ disorders with severe metabolic and neurological impact. A deeper comprehension of lysosomal composition and function, at both the cellular and organismal level, may uncover fundamental insights into human physiology and disease.
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Acknowledgements
C.S acknowledges the Italian Telethon funding agency, the European Research Council (ERC-101045285-AUTOSELECT) and the Italian Ministry of Health (PNRR-MAD-2022-12376672). R.M.P acknowledges the National Institutes of Health (NIH R01CA260249), the Ed Marra Passion to Win Fund, the Shorenstein Fund and the AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grant. The authors apologize to colleagues whose work they were unable to cite due to space restrictions.
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Settembre, C., Perera, R.M. Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology. Nat Rev Mol Cell Biol 25, 223–245 (2024). https://doi.org/10.1038/s41580-023-00676-x
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DOI: https://doi.org/10.1038/s41580-023-00676-x
