P441Defective SR-mitochondria interaction and Ca2+ transfer in aged mouse cardiomyocytes

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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.

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