Slow calcium waves and redox changes precede mitochondrial permeability transition pore opening in the intact heart during hypoxia and reoxygenation.

TitleSlow calcium waves and redox changes precede mitochondrial permeability transition pore opening in the intact heart during hypoxia and reoxygenation.
Publication TypeJournal Article
Year of Publication2012
AuthorsDavidson, SM, Yellon, DM, Murphy, MP, Duchen, MR
JournalCardiovasc Res
Volume93
Issue3
Pagination445-53
Date Published2012 Mar 01
ISSN1755-3245
KeywordsAnimals, Calcium Signaling, Cell Death, Hypoxia, Mice, Mitochondrial Membrane Transport Proteins, Mitochondrial Membranes, Myocardial Reperfusion Injury, Myocardium, Myocytes, Cardiac, Oxidation-Reduction, Perfusion, Rats
Abstract

AIMS: Opening of the mitochondrial permeability transition pore (mPTP) is an important step on the pathway towards cardiomyocyte death, defining the extent of injury following cardiac ischaemia and reperfusion. In isolated mitochondria, mPTP opening is triggered by calcium overload facilitated by oxidative stress. In isolated cells, however, it has been suggested that mPTP opening occurs before calcium overload and is stimulated by oxidative stress. Our objective was to establish the events that cause mPTP opening in the intact heart.METHODS AND RESULTS: We performed multiphoton imaging of Langendorff-perfused mouse hearts expressing an inducible, Ca(2+)-sensitive reporter (circularly Permuted GFP and calmodulin (CaM), version 2), to examine the spatiotemporal relationship between [Ca(2+)](c), redox state, and mPTP opening in the intact heart during hypoxia and reoxygenation at sub-myocyte resolution. We found that during reperfusion, calcium waves propagated across multiple cells at 3.3 µm/s. mPTP opening caused an abrupt loss of mitochondrial membrane potential, measured using a potentiometric dye, which was invariably preceded by a rise in [Ca(2+)](c). The probability that localized [Ca(2+)](c) waves led to mPTP opening was greater early during reoxygenation. During reoxygenation, coordinated redox changes also occurred across large regions and preceded mPTP opening on average by 122 ± 38 s. Fewer [Ca(2+)] waves led to mPTP opening in the presence of mPTP inhibitor cyclosporin A or mitochondrial-targeted scavenger of reactive oxygen species, MitoQ.CONCLUSION: These experiments define the spatiotemporal relationship between changes in [Ca(2+)](c), redox state and mPTP opening during reoxygenation in the intact heart. Tissue oxidation coincident with localized calcium waves together conspire to cause mPTP opening and subsequent cell death.

DOI10.1093/cvr/cvr349
Alternate JournalCardiovasc. Res.
Citation Key10.1093/cvr/cvr349
PubMed ID22198507
Grant ListEAA/17568 / / Medical Research Council / United Kingdom
PG/10/005/28175 / / British Heart Foundation / United Kingdom
RG/08/015/26411 / / British Heart Foundation / United Kingdom
MC_U105663142 / / Medical Research Council / United Kingdom
G0700933 / / Medical Research Council / United Kingdom