Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury.
When loaded with high (pathological) levels of Ca2+, mitochondria become swollen and uncoupled as the result of a large nonspecific increase in membrane permeability. This process, known as the mitochondrial permeability transition (MPT), is exacerbated by oxidative stress and adenine nucleotide depletion. These conditions match those that a heart experiences during reperfusion following a period of ischaemia. The MPT is caused by the opening of a non-specific pore that can be prevented by sub-micromolar concentrations of cyclosporin A (CsA). A variety of conditions that increase the sensitivity of pore opening to [Ca2+], such as thiol modification, oxidative stress, increased matrix volume and chaotropic agents, all enhance the binding of matrix cyclophilin (CyP) to the inner mitochondrial membrane in a CsA-sensitive manner. In contrast, ADP, membrane potential and low pH decrease the sensitivity of pore opening to [Ca2+] without affecting CyP binding. We present a model of pore opening involving CyP binding to a membrane target protein followed by Ca(2+)-dependent triggering of a conformational change to induce channel opening. Using the ischaemic/reperfused rat heart we have shown that the mitochondrial pore does not open during ischaemia, but does do so during reperfusion. Recovery of heart during reperfusion is improved in the presence of 0.2 microM CsA, suggesting that the MPT may be critical in the transition from reversible to irreversible reperfusion injury.
Halestrap
A P
AP
Bristol Heart Institute, University of Bristol, UK.
Connern
C P
CP
Griffiths
E J
EJ
Kerr
P M
PM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007425:Intracellular Membranes; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008933:Mitochondrial Swelling; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D011485:Protein Binding; D051381:Rats
D016572:Cyclosporine; D019696:Peptidylprolyl Isomerase; D002118:Calcium