Diolez Philippe, Bourdel-Marchasson Isabelle, Calmettes Guillaume, Pasdois Philippe, Detaille Dominique, Rouland Richard, Gouspillou Gilles
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.
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.
Front Physiol. 2015 Dec 16;6:369. doi: 10.3389/fphys.2015.00369. eCollection 2015.
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.
线粒体膜电位是线粒体功能的主要调节因子，包括偶联效率和活性氧（ROS）的产生。这两种功能对细胞生物能量学都至关重要。我们之前提供了证据，表明衰老过程中腺嘌呤核苷酸转位酶（ANT）会出现特定调节，导致膜电位降低——进而导致ROS产生减少——但令人惊讶的是，在低ATP周转率条件下偶联效率会增加。对老年和年轻大鼠骨骼肌（腓肠肌）分离线粒体的生物能量学参数（氧化和磷酸化速率、膜电位）进行仔细研究发现，在磷酸化系统水平上发生了重塑，而线粒体内膜（解偶联）或呼吸链复合物调节并未改变。我们进一步观察到，老年分离线粒体对ADP的线粒体亲和力降低，且ANT对其特异性抑制剂苍术苷的敏感性更高。与年轻肌肉相比，这种由年龄引起的ANT修饰导致维持相同ATP周转率所需的ADP浓度增加，因此在体内磷酸化条件下膜电位更低。因此，对于同等的ATP周转率（细胞ATP需求），老年肌肉线粒体中的偶联效率甚至更高，这是由于膜电位降低导致内膜质子泄漏下调所致。在衰老自由基理论的框架下，ANT功能的这些改变可能是线粒体内ROS引起的氧化损伤的结果，可能表现为一个良性循环，即ROS诱导一种机制来减少其产生，而不会导致解偶联，甚至提高效率。由于ROS作为治疗靶点的重要性，这种新机制值得进一步研究。
