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Preventing cell death with a ‘check valve’ in mitochondrial complex I?

Abstract : As the discovery that some mitochondrial proteins located between the inner and outer mitochondrial membranes promoted cell death once released into the cytosol, mitochondria have been acknowledged as key organelles in programmed cell death.1 One of the mechanisms triggering the release of mitochondrial pro-apoptotic proteins is the opening of an inner membrane channel named the permeability transition pore (PTP).2 Among the many parameters inducing PTP opening, oxidative stress is known to promote PTP opening in intact cells.3 The PTP is a multi-protein complex composed of a core (the channel itself) regulated by other proteins, including cyclophilin D that makes PTP opening easier by binding with the rest of the pore.4 The amount of cyclophilin D varies depending on tissues, which explains why drugs detaching cyclophilin D from the pore (e.g., Cyclosporine A) are less effective at PTP inhibition in tissues with low amounts of cyclophilin D.5 In all the tissues tested so far, the inhibition of respiratory chain complex I has been shown to inhibit PTP opening, either spontaneously (in tissues with low amount of cyclophilin D) or once cyclophilin D had been detached from the pore.5 Because both complex I inhibition and cyclophilin D detachment require phosphate to inhibit PTP opening, a model has been proposed in which the number of binding sites for phosphate depends on complex I activity, while the binding of phosphate is prevented by cyclophilin D
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Soumis le : jeudi 28 mai 2020 - 16:39:18
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Eric Fontaine, Dominique Detaille, Guillaume Vial. Preventing cell death with a ‘check valve’ in mitochondrial complex I?. Cell Death and Disease, Nature Publishing Group, 2016, 7 (3), pp.e2165-e2165. ⟨10.1038/cddis.2016.71⟩. ⟨hal-01962111⟩



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