The mitochondrial permeability transition pore and its role in cell death.
This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and inner membranes. In vitro, under pseudopathological conditions of oxidative stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore state allowing free diffusion of low-Mr solutes across the inner membrane. These conditions correspond to those that unfold during tissue ischaemia and reperfusion, suggesting that pore opening may be an important factor in the pathogenesis of necrotic cell death following ischaemia/reperfusion. Evidence that the pore does open during ischaemia/reperfusion is discussed. There are also strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can recruit a number of other proteins, including Bax, and that the complex is utilized in some capacity during apoptosis. The apoptotic pathway is amplified by the release of apoptogenic proteins from the mitochondrial intermembrane space, including cytochrome c, apoptosis-inducing factor and some procaspases. Current evidence that the pore complex is involved in outer-membrane rupture and release of these proteins during programmed cell death is reviewed, along with indications that transient pore opening may provoke 'accidental' apoptosis.
Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, U.K. m.crompton@biochemistry.ucl.ac.uk
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D000818:Animals; D017209:Apoptosis; D002463:Cell Membrane Permeability; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D006801:Humans; D020104:Immunophilins / Q000502:physiology*; D008928:Mitochondria / Q000473:pathology / Q000502:physiology; D018272:Porins / Q000502:physiology*; D050994:Voltage-Dependent Anion Channels
D000081406:Peptidyl-Prolyl Isomerase F; D018272:Porins; D050994:Voltage-Dependent Anion Channels; D021983:Cyclophilins; D020104:Immunophilins