Les espèces actives de l’oxygène : le yin et le yang de la mitochondrie Physiological and physiopathological consequences of mitochondrial reactive oxygen species

Résumé

Il existe de nombreuses sources d’espèces actives de l’oxygène (EAO) dans la cellule ; malgré l’importance de chacune d’entre elles, la mitochondrie a été choisie comme sujet central de cet article en raison de son rôle primordial dans la bio-énergétique et du fait qu’elle constitue le site majeur de la production cellulaire d’EAO, 80 % de l’anion superoxyde provenant de la chaîne respiratoire. Cette production est indissociable du processus respiratoire et fortement modulée par les conditions environnementales : elle varie notamment selon l’intensité du métabolisme énergétique ou de la pression en oxygène, permettant aux cellules de s’adapter à ces changements environnementaux en activant des voies spécifiques de signalisation. Lorsque cette production d’EAO devient chronique, elle induit des effets délétères, le stress oxydant mitochondrial étant impliqué aussi bien en physiopathologie qu’au cours du vieillissement.

Summary

Literature on reactive oxygen species (ROS) effects on cell biology and physiopathology is huge and appears to be controversial. This could be explained by the fact that very few studies take into account the real subcellular source of ROS production, their chemical nature and the intensity of their production. In spite of the importance of the other sites of ROS production in the cell, we decided to focus on mitochondrial ROS. Besides their key role in bioenergetics and ATP synthesis, mitochondria are one of the main sites of ROS generation within the cell. 80 % of intracellular superoxide anion is provided by the mitochondrial respiratory chain. Mitochondrial ROS production is closely associated with activity of the respiratory chain and is modulated by environmental factors which can induce constraints on respiratory chain components. Nutrient availability as well as oxygen pressure can both modulate mitochondrial ROS production. When moderately produced, ROS specifically regulate intracellular signalling pathways by reversible oxidation of proteins such as transcription factors or proteins kinases. In this way, they can trigger cell adaptation to environmental changes as modifications of energetic metabolism or hypoxia. Indeed, we demonstrated that mitochondrial ROS act as key elements in the control of white adipose tissue development by specific up-regulation of the anti-adipogenic transcription factor CHOP-10/GADD153. However, when they are produced at high level and in a chronic manner, mitochondrial ROS can also have deleterious effects by massive and irreversible oxidation of their principals targets i.e. lipids, DNA and proteins. In these conditions, mitochondrial ROS are involved in aging process and in pathological situations as metabolic disease.