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Protection of PC12 cells from cocaine-induced cell death by inhibiting mitochondrial permeability transition

Abstract : Cocaine abuse induces brain injury and neurodegeneration by a mechanism that has not yet been fully elucidated. Mitochondria play a key role in cell death processes, notably through the opening of the permeability transition pore (PTP). In this work, we examined the involvement of the PTP in cocaine-induced toxicity in PC12 cell lines. We used two different PTP inhibitors -i.e. cyclosporin A (CsA) and metformin-to assess their ability to counteract the cocaine induced effects. We first observed that a 48 h exposure to cocaine strongly sensitized cells to calcium overload, as measured by the calcium retention capacity. CsA and metformin significantly decreased the cocaine-induced PTP opening sensitization. We next showed by confocal microscopy that cocaine induced a permanent PTP opening in intact living cells, a phenomenon characterized by the collapse of the mitochondrial membrane potential and the relocation of the NAD(P)H from the mitochondrial matrix to the cytosol. As expected, a cocaine-induced PTP opening was prevented by PTP inhibitors. Finally, a flow cytometry analysis revealed that cocaine induced cell death while CsA and metformin promoted cell survival. Our results demonstrate that cocaine induces PC12 cell death through a mechanism involving permanent PTP opening.
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https://hal.univ-grenoble-alpes.fr/hal-01961994
Contributeur : Sarah Hamant <>
Soumis le : jeudi 20 décembre 2018 - 12:21:16
Dernière modification le : mercredi 7 octobre 2020 - 13:10:12

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Frédéric Lamarche, Cécile Cottet-Rousselle, Luc Barret, Eric Fontaine. Protection of PC12 cells from cocaine-induced cell death by inhibiting mitochondrial permeability transition. Neurochemistry International, Elsevier, 2017, 109, pp.34-40. ⟨10.1016/j.neuint.2017.04.010⟩. ⟨hal-01961994⟩

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