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The compound BTB06584 is an IF1 -dependent selective inhibitor of the mitochondrial F1 Fo-ATPase.

Abstract：

BACKGROUND AND PURPOSE:Ischaemia compromises mitochondrial respiration. Consequently, the mitochondrial F1 Fo-ATPsynthase reverses and acts as a proton-pumping ATPase, so maintaining the mitochondrial membrane potential (ΔΨm ), while accelerating ATP depletion and cell death. Here we have looked for a molecule that can selectively inhibit this activity without affecting ATP synthesis, preserve ATP and delay ischaemic cell death. EXPERIMENTAL APPROACH:We developed a chemoinformatic screen based on the structure of BMS199264, which is reported to selectively inhibit F1 Fo-ATPase activity and which is cardioprotective. Results suggested the molecule BTB06584 (hereafter referred to as BTB). Fluorescence microscopy was used to study its effects on ΔΨm and on the rate of ATP consumption following inhibition of respiration in several cell types. The effect of BTB on oxygen (O2 ) consumption was explored and protective potential determined using ischaemia/reperfusion assays. We also investigated a potential mechanism of action through its interaction with inhibitor protein of F1 subunit (IF1 ), the endogenous inhibitor of the F1 Fo-ATPase. KEY RESULTS:BTB inhibited F1 Fo-ATPase activity with no effect on ΔΨm or O2 consumption. ATP consumption was decreased following inhibition of respiration, and ischaemic cell death was reduced. BTB efficiency was increased by IF1 overexpression and reduced by silencing the protein. In addition, BTB rescued defective haemoglobin synthesis in zebrafish pinotage (pnt) mutants in which expression of the Atpif1a gene is lost. CONCLUSIONS AND IMPLICATIONS:BTB may represent a valuable tool to selectively inhibit mitochondrial F1 Fo-ATPase activity without compromising ATP synthesis and to limit ischaemia-induced injury caused by reversal of the mitochondrial F1 Fo-ATPsynthase.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Ivanes F,Faccenda D,Gatliff J,Ahmed AA,Cocco S,Cheng CH,Allan E,Russell C,Duchen MR,Campanella M

doi

10.1111/bph.12638

subject

Has Abstract

pub_date

2014-09-01 00:00:00

pages

4193-206

issue

eissn

0007-1188

issn

1476-5381

journal_volume

171

pub_type

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The compound BTB06584 is an IF1 -dependent selective inhibitor of the mitochondrial F1 Fo-ATPase.