title: Hypothesis on Skeletal Muscle Aging: Mitochondrial Adenine Nucleotide Translocator Decreases Reactive Oxygen Species Production While Preserving Coupling Efficiency.
abstract: Mitochondrial membrane potential is the major regulator of mitochondrial functions, including coupling efficiency and production of reactive oxygen species (ROS). Both functions are crucial for cell bioenergetics. We previously presented evidences for a specific modulation of adenine nucleotide translocase (ANT) appearing during aging that results in a decrease in membrane potential - and therefore ROS production-but surprisingly increases coupling efficiency under conditions of low ATP turnover. Careful study of the bioenergetic parameters (oxidation and phosphorylation rates, membrane potential) of isolated mitochondria from skeletal muscles (gastrocnemius) of aged and young rats revealed a remodeling at the level of the phosphorylation system, in the absence of alteration of the inner mitochondrial membrane (uncoupling) or respiratory chain complexes regulation. We further observed a decrease in mitochondrial affinity for ADP in aged isolated mitochondria, and higher sensitivity of ANT to its specific inhibitor atractyloside. This age-induced modification of ANT results in an increase in the ADP concentration required to sustain the same ATP turnover as compared to young muscle, and therefore in a lower membrane potential under phosphorylating-in vivo-conditions. Thus, for equivalent ATP turnover (cellular ATP demand), coupling efficiency is even higher in aged muscle mitochondria, due to the down-regulation of inner membrane proton leak caused by the decrease in membrane potential. In the framework of the radical theory of aging, these modifications in ANT function may be the result of oxidative damage caused by intra mitochondrial ROS and may appear like a virtuous circle where ROS induce a mechanism that reduces their production, without causing uncoupling, and even leading in improved efficiency. Because of the importance of ROS as therapeutic targets, this new mechanism deserves further studies.
authors.affiliation: INSERM U1045 - Centre de Recherche Cardio-Thoracique de Bordeaux and LIRYC, Institut de Rythmologie et Modélisation Cardiaque, Université de Bordeaux, CHU de Bordeaux Pessac, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Diolez
authors.affiliation: CHU de Bordeaux, Pôle de Gérontologie CliniqueBordeaux, France; Résonance Magnétique des Systèmes Biologiques, UMR 5536 Centre National de la Recherche Scientifique, Université de BordeauxBordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bourdel-Marchasson
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles Los Angeles, CA, USA.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Calmettes
authors.affiliation: INSERM U1045 - Centre de Recherche Cardio-Thoracique de Bordeaux and LIRYC, Institut de Rythmologie et Modélisation Cardiaque, Université de Bordeaux, CHU de Bordeaux Pessac, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pasdois
authors.affiliation: INSERM U1045 - Centre de Recherche Cardio-Thoracique de Bordeaux and LIRYC, Institut de Rythmologie et Modélisation Cardiaque, Université de Bordeaux, CHU de Bordeaux Pessac, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Detaille
authors.affiliation: Résonance Magnétique des Systèmes Biologiques, UMR 5536 Centre National de la Recherche Scientifique, Université de Bordeaux Bordeaux, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Rouland
authors.affiliation: Département des Sciences de l'activité Physique, Université du Québec À Montréal Montréal, QC, Canada.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gouspillou
keywords: adenosine nucleotide translocator; mitochondria; mitochondrial membrane potential; muscle energetics; oxygen free radicals; skeletal muscle aging