Mitochondrial targeting of cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation
Résumé
Cyclosporin A is a hydrophobic undecapeptide that inhibits cyclophilins, a family of peptidylprolyl cis-trans-isomerases. In some experimental models, cyclosporin A offers partial protection against lethal cell injury brought about by transient ischaemia; this is believed to reflect inhibition of cyclophilin-D, a mitochondrial isoform that facilitates formation of the permeability transition pore in the mitochondrial inner membrane. To evaluate this further, we have targeted cyclosporin A to mitochondria so that it becomes selective for cyclophilin-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 cyclosporin A itself) preferentially inhibited cyclophilin-D over extramitochondrial cyclophilin-A. In hippocampal neurons, mitochondrial targeting markedly enhanced the capacity of cyclosporin A 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 cyclophilin-D has a major pathogenic role in “energy failure”, but not in glutamate excitotoxicity, where cytoprotection primarily reflects cyclosporin A interaction with extramitochondrial cyclophilins and calcineurin. Moreover, the therapeutic potential of cyclosporin A against ischaemia / reperfusion injuries not involving glutamate may be improved by mitochondrial targeting.
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