Journal
CELL METABOLISM
Volume 3, Issue 3, Pages 649-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2021.01.014
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Funding
- American Cancer Society [IRG9512513]
- National Institute of General Medical Sciences [1R01GM115650]
- American Association for Cancer Research/Stand Up To Cancer [SU2CAACRIRG0116]
- UC Davis Comprehensive Cancer Center Support Grant (CCSG) - National Cancer Institute [NCI P30CA093373]
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Cell-to-cell heterogeneity in metabolism can resist the effects of OXPHOS inhibitors, leading to dynamic fluctuations in cellular energetic balance, with implications for predicting responses to OXPHOS inhibition.
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.
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