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Oligomycin-induced proton uncoupling.
Toxicology in Vitro ( IF 3.2 ) Pub Date : 2020-06-02 , DOI: 10.1016/j.tiv.2020.104907
Abby Hearne 1 , Haotong Chen 1 , Anna Monarchino 1 , Jeffrey S Wiseman 1
Affiliation  

Oligomycin is a classical mitochondrial reagent that binds to the proton channel on the Fo component of ATP synthase. As a result, oligomycin blocks mitochondrial ATP synthesis, proton translocation, and O2 uptake. Here we show that oligomycin induces proton uncoupling subsequent to inhibition of ATP synthesis, as evidenced by recovery of O2 uptake to near baseline levels. Uncoupling is uniquely rapid and readily observed in HepG2 cells but is also observed at longer times in the unrelated H1299 cell line. Proton fluxes plateau at oligomycin concentrations in the region 0.25–5 μM. At the plateau, fluxes are lower than expected for the classical mitochondrial permeability transition pore, although in H1229 cells, fluxes increase to levels consistent with pore opening at higher oligomycin concentrations. Uncoupling is observed in cells metabolizing either pyruvate or lactate and reversed by addition of glucose to restore ATP synthesis. Uncoupling is not sensitive to cyclosporin A and is not reversed by the ANT inhibitor bongkrekic acid. However, bongkrekic acid inhibits uncoupling if added before oligomycin, which we interpret in terms of maintenance of mitochondrial ATP levels.



中文翻译:

寡霉素诱导的质子解偶联。

寡霉素是一种经典的线粒体试剂,可与ATP合酶F o成分上的质子通道结合。结果,寡霉素会阻止线粒体ATP合成,质子易位和O 2吸收。在这里,我们显示寡霉素诱导抑制ATP合成后的质子解偶联,如O 2的回收所证明吸收到接近基线水平。解偶联是唯一快速的,并且在HepG2细胞中很容易观察到,但在不相关的H1299细胞系中也观察到了更长的时间。寡霉素浓度在0.25-5μM范围内,质子通量稳定。在高原地区,通量比经典线粒体通透性过渡孔的预期通量要低,尽管在H1229细胞中,通量增加到与寡聚霉素浓度较高时开孔相一致的水平。在代谢丙酮酸或乳酸的细胞中观察到解偶联,并通过添加葡萄糖逆转以恢复ATP合成。解偶联对环孢菌素A不敏感,并且不会被ANT抑制剂邦克里基酸逆转。但是,如果在寡霉素之前添加邦克雷奇酸,则会抑制解偶联,这是根据维持线粒体ATP水平来解释的。

更新日期:2020-06-02
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