1. Transient phases of OXPHOS inhibitor resistance reveal underlying metabolic heterogeneity in single cells
- Author
-
Carolyn Teragawa, Breanne Sparta, John G. Albeck, Michael Pargett, and Nont Kosaisawe
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Oligomycin ,Physiology ,mTORC1 ,Medical Biochemistry and Metabolomics ,AMP-Activated Protein Kinases ,PI3K ,Oxidative Phosphorylation ,chemistry.chemical_compound ,0302 clinical medicine ,Adenosine Triphosphate ,Extracellular Signal-Regulated MAP Kinases ,Chemistry ,Kinase ,metabolic cycle ,oscillation ,Cell biology ,Adenosine Diphosphate ,Signal transduction ,Signal Transduction ,oligomycin ,1.1 Normal biological development and functioning ,Antineoplastic Agents ,Oxidative phosphorylation ,translation regulation ,Mechanistic Target of Rapamycin Complex 1 ,Article ,Cell Line ,Endocrinology & Metabolism ,03 medical and health sciences ,Underpinning research ,Humans ,insulin signaling ,Molecular Biology ,Protein kinase B ,mammalian target of rapamycin ,AKT ,electron transport chain ,G1 Phase ,AMPK ,Cell Biology ,030104 developmental biology ,Glucose ,Protein Biosynthesis ,FRET ,adenosine mono-phosphate-regulated protein kinase ,Generic health relevance ,Biochemistry and Cell Biology ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2019