Hypothesis on Skeletal Muscle Aging: Mitochondrial Adenine Nucleotide Translocator Decreases Reactive Oxygen Species Production While Preserving Coupling Efficiency.

Philippe Diolez,Richard Rouland,Guillaume Calmettes,Philippe Pasdois,Dominique Detaille,Isabelle Bourdel-Marchasson,Gilles Gouspillou

doi:10.3389/fphys.2015.00369

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.

Highlights

Mitochondria, because of their central role in ATP supply through oxidative phosphorylation, and in oxygen radical production and ion homeostasis, play a crucial role in skeletal muscle function
The main observation to be made here is represented by the dashed lines, which illustrate that for a given phosphorylation rate the membrane potential value is always lower in mitochondria from aged rats
We could observe that the elasticity of both modules changed with membrane potential value, but while the curves are superimposed for substrate oxidation, they appeared significatively different for phosphorylation, especially for high values of ψ, ranging from 160 to 180 mV, corresponding to low phosphorylation activity and higher proton leak, likely to be the most common situation in vivo

Summary

Introduction

Mitochondria, because of their central role in ATP supply through oxidative phosphorylation, and in oxygen radical production and ion homeostasis, play a crucial role in skeletal muscle function. The accepted view hypothesizes that the reactive oxygen species (ROS) production linked to the activity of respiratory chain is responsible for the damages accumulated with aging to several components of the oxidative phosphorylation machinery and mitochondrial DNA (Dirks et al, 2006; Gonzalez-Freire et al, 2015) and triggers atrophy of the muscles (Dirks et al, 2006) These damages are mainly thought to result in mitochondrial dysfunction which disables the capacity of mitochondria to fulfill cellular ATP demand during contraction (Dirks et al, 2006; Bratic and Trifunovic, 2010). ROS production and related damages are considered responsible for loss of muscle mass and function during aging

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