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Mitochondrial targeting of cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation

Malouitre, S.; Dube, H.; Selwood, D.; Crompton, M.; (2009) Mitochondrial targeting of cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation. Biochemical Journal , 425 (1) pp. 137-148. 10.1042/BJ20090332. Green open access

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Abstract

CsA (cyclosporin A) is a hydrophobic undecapeptide that inhibits CyPs (cyclophilins), a family of PPIases (peptidylprolyl cis–trans isomerases). In some experimental models, CsA offers partial protection against lethal cell injury brought about by transient ischaemia; this is believed to reflect inhibition of CyP-D, a mitochondrial isoform that facilitates formation of the permeability transition pore in the mitochondrial inner membrane. To evaluate this further, we have targeted CsA to mitochondria so that it becomes selective for CyP-D in cells. This was achieved by conjugating the inhibitor to the lipophilic triphenylphosphonium cation, enabling its accumulation in mitochondria due to the inner membrane potential. In a cell-free system and in B50 neuroblastoma cells the novel reagent (but not CsA itself) preferentially inhibited CyP-D over extramitochondrial CyP-A. In hippocampal neurons, mitochondrial targeting markedly enhanced the capacity of CsA to prevent cell necrosis brought about by oxygen and glucose deprivation, but largely abolished its capacity to inhibit glutamate-induced cell death. It is concluded that CyP-D has a major pathogenic role in ‘energy failure’, but not in glutamate excitotoxicity, where cytoprotection primarily reflects CsA interaction with extramitochondrial CyPs and calcineurin. Moreover, the therapeutic potential of CsA against ischaemia/reperfusion injuries not involving glutamate may be improved by mitochondrial targeting.

Type: Article
Title: Mitochondrial targeting of cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation
Open access status: An open access version is available from UCL Discovery
DOI: 10.1042/BJ20090332
Publisher version: http://dx.doi.org/10.1042/BJ20090332
Language: English
Additional information: © 2010 The Authors. The authors have paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Cyclophilin (CyP), cyclosporin A (CsA), glutamate toxicity, hippocampal neuron, ischaemia, necrosis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/20029
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