부산대학교 도서관

Mitochondrial alterations are critically involved in the increased susceptibility to disease of the aging heart. We investigated the role of sarcoplasmic reticulum (SR)-mitochondria communication in myocardial calcium handling during aging.Methods and results: In subsarcolemmal and interfibrillar mitochondria isolated from old (>20 months) and young (<6 months) mouse hearts no differences in resting respiration through the different complexes were detected, but maximal ADP-stimulated O2 consumption was reduced in aged interfibrillar mitochondria. Accordingly, resting mitochondrial membrane potential in cardiomyocytes and ATP/phosphocreatine in intact myocardium (NMR spectroscopy) were preserved in old mice. Second generation proteomics disclosed an increase in mitochondrial protein oxidation during aging. Since mitochondrial Ca2+ regulates both energy production and oxidative status, we investigated whether aging affects mitochondrial Ca2+ uptake. No age-dependent differences were found in Ca2+ uptake kinetics in isolated mitochondria. By contrast, mitochondrial Ca2+ uptake resulting from SR transfer was significantly reduced in old cardiomyocytes, despite no changes in SR Ca2+ content. Immunocolocalization and proximity ligation assay identified defective communication between mitochondrial VDAC and SR ryanodine receptor (RyR) during aging, with adverse functional consequences on SR (Ca2+ transients and sparks). Age-dependent alterations in SR Ca2+ transfer to mitochondria could be reproduced in young cardiomyoctes after pharmacological disruption of the connection between both organelles, an intervention that had no effect in old cardiomyocytes or isolated mitochondria.Conclusion: Defective SR-mitochondria communication underlies inefficient Ca2+ exchange between both organelles that could be responsible, at least in part, for inadequate energy demand/supply matching in the aging heart.