Transient phases of OXPHOS inhibitor resistance reveal underlying metabolic heterogeneity in single cells.
| Autor: | Kosaisawe N; Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA., Sparta B; Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA., Pargett M; Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA., Teragawa CK; Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA., Albeck JG; Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA. Electronic address: jgalbeck@ucdavis.edu. |
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| Jazyk: | angličtina |
| Zdroj: | Cell metabolism [Cell Metab] 2021 Mar 02; Vol. 33 (3), pp. 649-665.e8. Date of Electronic Publication: 2021 Feb 08. |
| DOI: | 10.1016/j.cmet.2021.01.014 |
| Abstrakt: | Cell-to-cell heterogeneity in metabolism plays an unknown role in physiology and pharmacology. To functionally characterize cellular variability in metabolism, we treated cells with inhibitors of oxidative phosphorylation (OXPHOS) and monitored their responses with live-cell reporters for ATP, ADP/ATP, or activity of the energy-sensing kinase AMPK. Across multiple OXPHOS inhibitors and cell types, we identified a subpopulation of cells resistant to activation of AMPK and reduction of ADP/ATP ratio. This resistant state persists transiently for at least several hours and can be inherited during cell divisions. OXPHOS inhibition suppresses the mTORC1 and ERK growth signaling pathways in sensitive cells, but not in resistant cells. Resistance is linked to a multi-factorial combination of increased glucose uptake, reduced protein biosynthesis, and G0/G1 cell-cycle status. Our results reveal dynamic fluctuations in cellular energetic balance and provide a basis for measuring and predicting the distribution of cellular responses to OXPHOS inhibition. Competing Interests: Declaration of interests J.G.A. has received research grants from Kirin Corporation. The other authors declare no competing interests. (Copyright © 2021 Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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