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Uncoupling effect of bafilomycin A1 on HIF and cell bioenergetics
Author(s) -
Dmitriev Ruslan I,
Zhdanov Alexander V,
Papkovsky Dmitri B
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.861.15
Subject(s) - valinomycin , bafilomycin , bioenergetics , nigericin , ionophore , membrane potential , mitochondrion , microbiology and biotechnology , intracellular , oligomycin , chemistry , hypoxia (environmental) , uncoupling agents , cell , atpase , biophysics , biochemistry , biology , oxygen , autophagy , apoptosis , membrane , enzyme , organic chemistry
The inhibitors of the V‐ATPase, bafilomycin A1 (Baf) and concanamycin A (CMA) are widely used drugs in cell physiology studies as well as pre‐clinical trials. We showed for the first time that Baf can uncouple mitochondria in vivo (acting as potassium ionophore) thereby decreasing the mitochondrial membrane potential, pH and Ca 2+ . At the same time, the observed effects of CMA were related to inhibition of V‐ATPase only. Here we demonstrate that such an uncoupling activity of Baf strongly affects cell bioenergetics and hypoxia‐dependent regulatory pathways in PC12 and HCT116 cells. We show that the mechanism of uncoupling by Baf differs from that of other potassium ionophore, valinomycin: cells, treated with Baf remain in state of “mild uncoupling”, having increased basal respiration and partially depolarized mitochondria for hours. The cells treated with Baf (but not with valinomycin) are capable to respond to FCCP treatment by further increase in respiration. Intracellular O 2 levels were strongly decreased upon Baf treatment at hypoxia. In these conditions Baf treatment leads to stabilization of HIF1a in HCT116 or HIF2a in PC12 cells independently on V‐ATPase inhibition. Thus, treatment with Baf may trigger hypoxia‐specific gene expression, which leads to cell adaptation to the conditions of low O 2 availability, and can have effects on cell bionergetics unrelated to inhibition of V‐ATPase. Supported by SFI.