2021年2月8日，《细胞-代谢》杂志在线发表了美国加州大学John G. Albeck课题组的最新研究。他们发现瞬时氧化磷酸化（OXPHOS）抑制剂耐药阶段揭示了单细胞潜在的代谢异质性。

为了在功能上表征代谢过程的细胞异质性，研究人员使用氧化磷酸化抑制剂（OXPHOS）处理了细胞，并用活细胞标志分子ATP、ADP/ATP或能量敏感激酶AMPK的活性监测了它们的反应。在不同OXPHOS抑制剂和细胞类型中，研究人员鉴定了对AMPK激活和ADP/ATP比降低具有抗性的细胞亚群。这种抗性状态会持续至少几个小时，并且可以通过细胞分裂遗传。

OXPHOS抑制可抑制敏感细胞中的mTORC1和ERK生长信号通路，但在抗性细胞中则无功能。抗药性与葡萄糖摄取增加、蛋白质生物合成减少和G0/G1细胞周期状态的多因素组合有关。该研究结果揭示了细胞能量平衡的动态波动，并为测量和预测对OXPHOS抑制细胞反应的分布提供了基础。

研究人员介绍，此前人们并不清楚代谢过程中细胞间的异质性在生理和药理中的作用。

附：英文原文

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

Author: Nont Kosaisawe, Breanne Sparta, Michael Pargett, Carolyn K. Teragawa, John G. Albeck

Issue&Volume: 2021-02-08

Abstract: Cell-to-cell heterogeneity in metabolism plays an unknown role in physiology and pharmacology.To functionally characterize cellular variability in metabolism, we treated cellswith inhibitors of oxidative phosphorylation (OXPHOS) and monitored their responseswith live-cell reporters for ATP, ADP/ATP, or activity of the energy-sensing kinaseAMPK. Across multiple OXPHOS inhibitors and cell types, we identified a subpopulationof cells resistant to activation of AMPK and reduction of ADP/ATP ratio. This resistantstate persists transiently for at least several hours and can be inherited duringcell divisions. OXPHOS inhibition suppresses the mTORC1 and ERK growth signaling pathwaysin sensitive cells, but not in resistant cells. Resistance is linked to a multi-factorialcombination of increased glucose uptake, reduced protein biosynthesis, and G0/G1 cell-cyclestatus. Our results reveal dynamic fluctuations in cellular energetic balance andprovide a basis for measuring and predicting the distribution of cellular responsesto OXPHOS inhibition.

DOI: 10.1016/j.cmet.2021.01.014

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00014-0