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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/H1281    most recent 00435.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ruiz-Meana, M. Articles by Garcia-Dorado, D. PubMed PubMed Citation Articles by Ruiz-Meana, M. Articles by Garcia-Dorado, D.

Role of sarcoplasmic reticulum in mitochondrial permeability transition and cardiomyocyte death during reperfusion

Servicio de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain

Submitted May 8, 2009 ; accepted in final form August 10, 2009

There is solid evidence that a sudden change in mitochondrial membrane permeability (mitochondrial permeability transition, MPT) plays a critical role in reperfusion-induced myocardial necrosis. We hypothesized that sarcoplasmic reticulum (SR) Ca²⁺ cycling may induce partial MPT in microdomains of close anatomic proximity between mitochondria and SR, resulting in hypercontracture and cell death. MPT (mitochondrial calcein release), cell length, and sarcolemmal rupture (Trypan blue and lactate dehydrogenase release) were measured in adult rat cardiomyocytes submitted to simulated ischemia (NaCN/2-deoxyglucose, pH 6.4) and reperfusion. On simulated reperfusion, 83 ± 2% of myocytes developed hypercontracture. In 22 ± 6% of cases, hypercontracture was associated with sarcolemmal disruption [Trypan blue(+)]. During simulated reperfusion there was a 25% release of cyclosporin A-sensitive mitochondrial calcein (with respect to total mitochondrial calcein content). Simultaneous blockade of SR Ca²⁺ uptake and release with thapsigargin and ryanodine, respectively, significantly reduced mitochondrial calcein release, hypercontracture, and cell death during simulated reperfusion. SR Ca²⁺ blockers delayed mitochondrial Ca²⁺ uptake in digitonin-permeabilized cardiomyocytes but did not have any effect on isolated mitochondria. Pretreatment with colchicine to disrupt microtubule network reduced the degree of fluorescent overlap between SR and mitochondria and abolished the protective effect of SR Ca²⁺ blockers on MPT, hypercontracture, and cell death during reperfusion. We conclude that SR Ca²⁺ cycling during reperfusion facilitates partial mitochondrial permeabilization due to the close anatomic proximity between both organelles, favoring hypercontracture and cell death.

calcium; mitochondria; hypercontracture