Development of mitochondrial permeability transition inhibitory agents: a novel drug target

Apoptosis is a genetically conserved mechanism that eliminates unnecessary or surplus cells and is also involved in the pathomechanism of a wide variety of diseases. The intrinsic pathway of apoptosis includes the mitochondria where numerous pro-apoptotic proteins are sequestered and their release marks the point-of-no-return, indicating the ultimate commitment to cell death. The mitochondrial permeability transition (mPT) is a mechanism enabling the release of Cytochrome-c (Cyt-c), AIF and other pro-apoptotic proteins, and is characterized by an alteration in the permeability of the organelle's membrane. This is due to reactive oxygen species or Ca(2+) triggered dynamic assemble of a trans bi-membrane channel from various protein components including the voltage dependent anion channel, the adenine nucleotide translocase, the cyclophyllin D that enables solutes up to 1.5 kDa to pass through. The resultant influx of water into the mitochondrial matrix leads to mitochondrial swelling and the rupture of the membranes. Numerous agents can inhibit mPT including amiodarone, a widely used antiarrhythmic agent. Modification of this benzofuran derivate with nitroxides or their secondary amine derivates that exhibits antioxidant properties leads to the enhancement of mPT inhibitory effect of the original compound. Furthermore this hybrid compound is also capable of influencing the necrotic cell death pathway. This strategy may prove to be beneficial to increase the effectiveness of other mPT inhibitory agents. However, further studies are necessary to identify the components and structure of the permeability transition pore in order to design more effective mPT inhibitory compounds to fully exploit the therapeutic potential of this novel drug target.