Mitochondrial permeability transition pore MPTP

Fig. 21.14. The mitochondrial permeability transition pore (MPTP). In the MPTP, ANT is thought to complex with VDAC. The conformation of ANT is regulated by cyclophilin D (CD), and Ca. VDACs bind a number of proteins, including Bcl2 and Bax, which regulate apoptosis. The change to an open pxrre is activated by Ca, depletion of adenine nucleotides, and oxygen radicals (ROS) that alter SH groups. It is inhibited by the electrochemical potential gradient (Ap), by cytosolic ATP, and by a low cytosolic pH.

Although tumor cell death is controlled by several mechanisms, one of the dominant mechanisms involves mitochondria [91], It is thus rational to target the mitochondria for therapeutic purposes due to its critical role in the regulation of apoptosis. One potential target is the mitochondrial permeability transition pore (MPTP), the most significant component of which appears to be the peripheral benzodiazepine receptor known as the translocator protein [92]. Various ligands for the translocator protein have shown both anti-proliferative and pro-apoptotic activity or may act as chemo-sensitizers via modulation of MPTP [93-95]. 

In male rat hepatocytes incubated with 100 pg/ml of diterpenoids from skullcap, the compounds caused apoptosis. Reactive metabolites formed by GYP3A depleted cellular thiols, increasing cellular calcium and opening the mitochondrial permeability transition pore (MPTP). Cyclosporine A, an inhibitor of MPTP opening, prevented cytochrome c release, caspase activation, and apoptosis, and caspase inhibitors also prevented apoptosis (Haouzi et al. 2000). 

The mitochondrial permeability transition (MPT) is the loss of the inner mitochondrial membrane impermeability to solutes caused by opening of the MPT pore (MPTP). In turn, this action results in a loss of mitochondrial function and provides a common mechanism implicated in activation of mi-tophagy/autophagy, apoptosis, and necrosis in different cell systems. Although the composition of MPTP is not fully settled, multiple studies suggest involvement of adenine nucleotide translocase (ANT) in the inner mitochondrial membrane, voltage-dependent anion channel (VDAC or porin) in the outer membrane, and cyclophilin D (CypD) in the matrix. 

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