title: Defective sarcoplasmic reticulum-mitochondria calcium exchange in aged mouse myocardium.
abstract: 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 (>20 months) with respect to young mice (5-6 months). Mitochondrial membrane potential and resting O2 consumption were similar in mitochondria from young and old hearts. However, maximal ADP-stimulated O2 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.
authors.affiliation: Cardiología, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Fernandez-Sanz
authors.affiliation: Cardiología, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Ruiz-Meana
authors.affiliation: Cardiología, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Miro-Casas
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Nuñez
authors.affiliation: Cardiología, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Castellano
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Loureiro
authors.affiliation: Cardiología, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Barba
authors.affiliation: Cardiología, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Poncelas
authors.affiliation: Cardiología, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rodriguez-Sinovas
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Vázquez
authors.affiliation: Cardiología, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Garcia-Dorado
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D050994:Voltage-Dependent Anion Channels; D000244:Adenosine Diphosphate; D010100:Oxygen; D002118:Calcium