OXPHOS抑制剂耐药的瞬时阶段揭示了单细胞潜在的代谢异质性

Transient phases of OXPHOS inhibitor resistance reveal underlying metabolic heterogeneity in single cells

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|核心内容：

细胞间代谢的异质性在生理学和药理学中起着未知的作用。

为了从功能上表征新陈代谢中的细胞多样性，我们用氧化磷酸化(OXPHOS)抑制剂处理细胞，并监测活细胞ATP、ADP/ATP或能量敏感激酶AMPK活性。

在多种OXPHOS抑制剂和细胞类型中，我们确定了一组细胞亚群，它们抵抗AMPK的激活和ADP/ATP比率的降低。

这种抗性状态持续至少几个小时，并可在细胞分裂过程中遗传。

OXPHOS抑制可抑制敏感细胞中的mTORC1和ERK生长信号通路，但不能抑制耐药细胞中的mTORC1和ERK生长信号通路。

耐药性与葡萄糖摄取增加、蛋白质生物合成减少以及G0/G1细胞周期状态等多因素综合作用有关。

我们的结果揭示了细胞能量平衡的动态波动，并为测量和预测细胞对OXPHOS抑制的反应分布提供了基础。

原文摘要：

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.

耐药就是顽强抵抗的表现，但是只持续几个小时，说明OXPHOS抑制剂过于强大，势不可挡。

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参考文献：10.1016/j.cmet.2021.01.014

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