Role of the mitochondrial membrane permeability transition in cell death |
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Authors: | Yoshihide Tsujimoto Shigeomi Shimizu |
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Institution: | (1) Osaka University Medical School, Department of Medical Genetics, SORST of the Japan Science and Technology Agency, 2-2 Yamadaoka, Suita Osaka, 565-0871, Japan |
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Abstract: | In recent years, the role of the mitochondria in both apoptotic and necrotic cell death has received considerable attention.
An increase of mitochondrial membrane permeability is one of the key events in apoptotic or necrotic death, although the details
of the mechanism involved remain to be elucidated. The mitochondrial membrane permeability transition (MPT) is a Ca2+-dependent increase of mitochondrial membrane permeability that leads to loss of Δψ, mitochondrial swelling, and rupture of
the outer mitochondrial membrane. The MPT is thought to occur after the opening of a channel that is known as the permeability
transition pore (PTP), which putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator
(ANT), cyclophilin D (Cyp D: a mitochondrial peptidyl prolyl-cis, trans-isomerase), and other molecule(s). Recently, significant progress has been made by studies performed with mice lacking Cyp
D at several laboratories, which have convincingly demonstrated that Cyp D is essential for the MPT to occur and that the
Cyp D-dependent MPT regulates some forms of necrotic, but not apoptotic, cell death. Cyp D-deficient mice have also been used
to show that the Cyp D-dependent MPT plays a crucial role in ischemia/reperfusion injury. The anti-apoptotic proteins Bcl-2
and Bcl-xL have the ability to block the MPT, and can therefore block MPT-dependent necrosis in addition to their well-established ability
to inhibit apoptosis. |
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Keywords: | Apoptosis Necrosis Mitochondria Cyclophilin D Cyclosporin A Membrane permeability transition Cytochrome c Ischemia |
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