The Mitochondrial Permeability Transition - A Pore Way for the Heart to Die

Journal of Clinical and Basic Cardiology 2002; 5 (1): 29-41

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Keywords: Adeninnukleotidtranslokase,  cyclophilin-D,  Kalzium-Overload,  mitochondriale Permeabilitäts-Transitions-Pore,  Oxidativer Stress,  Reperfusionsschaden,  adenine nucleotide translocase,  calcium overload,  cyclophilin-D,  mitochondrial permeability transition pore,  oxidative stress,  reperfusion injury

In reperfusion injury the mitochondria change from being the major ATP producers that sustain heart cell function to instruments of cell death. The molecular basis of this transition is the opening of a non-specific pore in the inner mitochondrial membrane, known as the permeability transition pore (MPTP). The MPTP is thought to be formed by a Ca-triggered conformational change of the adenine nucleotide translocase (ANT) that is facilitated by the binding of matrix cyclophilin-D (CyP-D). The process is greatly enhanced by oxidative stress and adenine nucleotide deprivation, conditions associated with reperfusion after a period of ischaemia. Opening of the MPTP causes swelling and uncoupling of mitochondria which, unrestrained, leads to necrosis. We have developed a technique to demonstrate directly that the MPTP opens during reperfusion of the ischaemic heart, but not during ischaemia itself. Recovery of hearts correlates with subsequent closure of the pore, and agents that prevent opening or enhance closure such as cyclosporin A, free radical scavengers (eg pyruvate and propofol) and low pH protect from injury. Mg2+ is another inhibitor of the MPTP (competitive with Ca2+) and this may be one aspect of the protective effect of Mg2+. No data are available on whether ischaemic preconditioning exerts its protective effects by inhibiting pore opening. In addition to its role in necrosis, transient MPTP opening may be involved in apoptosis through the release of cytochrome c and other pro-apoptotic molecules. These then activate the caspase that sets apoptosis in motion. However, only if subsequent MPTP closure occurs will ATP levels be maintained, ensuring that cell death continues down an apoptotic rather than a necrotic pathway.