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oai:repisalud.isciii.es:20.500.12105/55352024-10-31T11:47:14Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Fernandez-Sanz, C. author Ruiz-Meana, Marisol author Miro-Casas, E. author Nunez, Estefania author Castellano, J. author Loureiro, Marta author Barba, Ignasi author Poncelas, M. author Rodriguez-Sinovas, A. author Vazquez, Jesus author Garcia-Dorado, David author 2014 Mitochondrial alterations are critically involved in increased vulnerability to disease during aging. We investigated the contribution of mitochondria-sarcoplasmic reticulum (SR) communication in cardiomyocyte functional alterations during aging. Heart function (echocardiography) and ATP/phosphocreatine (NMR spectroscopy) were preserved in hearts from old mice (420 months) with respect to young mice (5-6 months). Mitochondrial membrane potential and resting O-2 consumption were similar in mitochondria from young and old hearts. However, maximal ADP-stimulated O-2 consumption was specifically reduced in interfibrillar mitochondria from aged hearts. Second generation proteomics disclosed an increased mitochondrial protein oxidation in advanced age. Because energy production and oxidative status are regulated by mitochondrial Ca2+, we investigated the effect of age on mitochondrial Ca2+ uptake. Although no age-dependent differences were found in Ca2+ uptake kinetics in isolated mitochondria, mitochondrial Ca2+ uptake secondary to SR Ca2+ release was significantly reduced in cardiomyocytes from old hearts, and this effect was associated with decreased NAD(P)H regeneration and increased mitochondrial ROS upon increased contractile activity. Immunofluorescence and proximity ligation assay identified the defective communication between mitochondrial voltage-dependent anion channel and SR ryanodine receptor (RyR) in cardiomyocytes from aged hearts associated with altered Ca2+ handling. Age-dependent alterations in SR Ca2+ transfer to mitochondria and in Ca2+ handling could be reproduced in cardiomyoctes from young hearts after interorganelle disruption with colchicine, at concentrations that had no effect in aged cardiomyocytes or isolated mitochondria. Thus, defective SR-mitochondria communication underlies inefficient interorganelle Ca2+ exchange that contributes to energy demand/supply mistmach and oxidative stress in the aged heart. Cell Death Dis. 2014; 5:e1573 10.1038/cddis.2014.526 2041-4889 CELL DEATH \& DISEASE 25522267 http://hdl.handle.net/20.500.12105/5535 TRAP MASS-SPECTROMETRY QUANTITATIVE PROTEOMICS ENDOPLASMIC-RETICULUM RYANODINE RECEPTORS CARDIAC MYOCYTES OXIDATIVE STRESS HEART-FAILURE INTERFIBRILLAR MITOCHONDRIA PERMEABILITY TRANSITION REDOX MODIFICATION Defective sarcoplasmic reticulum-mitochondria calcium exchange in aged mouse myocardium