Regulated and unregulated mitochondrial permeability transition pores: A new paradigm of pore structure and function?

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Abstract

Cyclosporin A (CsA) inhibits the mitochondrial permeability transition (MPT), but not always. To characterize the CsA-sensitive and -insensitive MPT, rat liver mitochondria were exposed to low and high doses of various MPT inducers. Mitochondrial swelling, cyclophilin D membrane binding and permeability transition (PT) pore diameter were measured. The results indicate two conductance modes for the PT pore: one activated by Ca2+ and inhibited by CsA and Mg2+ and the other unregulated. We propose a new model of pore formation and gating in which PT pores form by aggregation of misfolded integral membrane proteins damaged by oxidant and other stresses. Chaperone-like proteins initially block conductance through these misfolded protein clusters; however, increased Ca2+ opens these regulated PT pores, an effect blocked by CsA. When protein clusters exceed chaperones available to block conductance, unregulated pore opening occurs. © 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

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He, L., & Lemasters, J. J. (2002). Regulated and unregulated mitochondrial permeability transition pores: A new paradigm of pore structure and function? FEBS Letters, 512(1–3), 1–7. https://doi.org/10.1016/S0014-5793(01)03314-2

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