Abstract
Metabolism has historically been studied at the levels of whole cells, whole tissues and whole organisms. As a result, our understanding of how compartmentalization—the spatial and temporal separation of pathways and components—shapes organismal metabolism remains limited. At its essence, metabolic compartmentalization fulfils three important functions or ‘pillars’: establishing unique chemical environments, providing protection from reactive metabolites and enabling the regulation of metabolic pathways. However, how these pillars are established, regulated and maintained at both the cellular and systemic levels remains unclear. Here we discuss how the three pillars are established, maintained and regulated within the cell and discuss the consequences of dysregulation of metabolic compartmentalization in human disease. Organelles are increasingly emerging as ‘command-and-control centres’ and the increased understanding of metabolic compartmentalization is revealing new aspects of metabolic homeostasis, with this knowledge being translated into therapies for the treatment of cancer and certain neurodegenerative diseases.
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Acknowledgements
We thank M. Abu-Remaileh, H. Adelman, W. Chen, S. Hui, D. Lamming, B. Manning, D. Sabatini and T. Walther for comments and suggestions. We thank J. Gosse for editing. We apologize to our colleagues in the field for not being able to cite important contributions owing to space limitations.
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N.K. and L.B.-P. conceived and prepared the original draft and revised the manuscript.
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N.K. is funded by National Institutes of Health (NIH) R00 CA241332 and the Damon Runyon Cancer Research Foundation (73-22). L.B.-P. is funded by the Damon Runyon Cancer Research Foundation (62-20), the American Association for Cancer Research (19-20-45-BARP), the American Cancer Society, the Melanoma Research Alliance, the Ludwig Cancer Center of Harvard Medical School, Lungevity, ALK Positive, V-Foundation, Mary Kay Foundation, Paula and Rodger Riney Foundation and the NIH/National Cancer Institute (1R21CA226082-01, R37CA260062). L.B-P. is a founder and consultant of and holds privately held equity in Scorpion Therapeutics.
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Bar-Peled, L., Kory, N. Principles and functions of metabolic compartmentalization. Nat Metab 4, 1232–1244 (2022). https://doi.org/10.1038/s42255-022-00645-2
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DOI: https://doi.org/10.1038/s42255-022-00645-2
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