Abstract
The combination of calcium overload and oxidative stress opens a non-specific pore in the inner mitochondrial membrane known as the mitochondrial permeability transition pore (MPTP). This uncouples oxidative phosphorylation and compromises intracellular ATP levels eventually leading to necrotic cell death. In cardiac ischemia and reperfusion, as during treatment of a coronary thrombosis or cardiac surgery, the extent of MPTP opening determines the amount of irreversible damage (infarct size). Furthermore, cardioprotection can be achieved by inhibiting MPTP opening either directly with cyclosporin A analogues, or indirectly by reducing oxidative stress. The detailed molecular mechanism of the MPTP remains uncertain. Knockout studies have confirmed important regulatory roles for cyclophilin-D (CyP-D) and the adenine nucleotide translocase (ANT) but not the voltage dependent anion channel. Our own studies have implicated a calcium-triggered conformational change of the mitochondrial phosphate carrier that is facilitated by CyP-D and modulated by the conformation of the ANT.
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Halestrap, A.P. Mitochondria and reperfusion injury of the heart—A holey death but not beyond salvation. J Bioenerg Biomembr 41, 113–121 (2009). https://doi.org/10.1007/s10863-009-9206-x
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DOI: https://doi.org/10.1007/s10863-009-9206-x