Cancer is a leading cause of death in the western world and is increasing in frequency world-wide. Although diagnosis, treatment and therapeutic approaches to cancer have improved, many types of cancer are still lethal due to the lack of radical treatment. One of the fatal neoplastic disease types with poor prognosis is represented by malignant mesothelioma (MM). MM is characterised by very high mortality rate and limited therapeutic options. The etiology of the disease is mainly associated with exposure to asbestos fibres. The incidence of MM is increasing in many countries. The search for novel molecular targets, anti-cancer strategies and drugs, which would considerably improve the treatment is of great importance. Certain new drugs, especially those with specific molecular targets, show high selectivity in their action to cancer cells, and have considerably increased the cure rate in some types of cancer. Mitochondria have recently emerged as a very promising target for anti-cancer agents. A group of compounds with anti-cancer activity that induce apoptosis by way of mitochondrial destabilisation, termed 'mitocans', have been a recent focus of research. Several mitocans have been shown to selectively induce apoptosis in cancer cells and suppress the growth of many types of carcinomas in...

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En fournissant l’énergie nécessaire au métabolisme, la phosphorylation oxydative (OXPHOS) est un processus essentiel pour la plupart des organismes vivants. Pour faire face à diverses conditions métaboliques, l’efficacité des chaines respiratoires de la membrane composant l’OXPHOS doit être optimisée. Il est donc important de déterminer les mécanismes qui permettent de réguler l’efficacité de l’OXPHOS en fonction des besoins métaboliques.La question posée est la suivante : existe-t-il une organisation particulière des acteurs de l’OXPHOS dans la membrane des procaryotes qui puisse réguler l’activité de l’OXPHOS ?J’ai étudié l’organisation spatio-temporelle d‘un complexe respiratoire majeur de l’anaérobiose, la nitrate réductase NarGHI chez E. coli. Après avoir créé les outils pour la visualisation de ce complexe dans la cellule, j’ai montré l’existence d’une microcompartimentation de NarGHI aux pôles de la cellule lors d’une respiration en anaérobiose par microscopie optique à fluorescence. Dans un deuxième temps, j’ai montré le caractère dynamique de cette localisation en fonction des conditions métaboliques. L’anaérobiose et la présence d’un ∆pH suffisant sont des éléments requis pour permettre ce niveau d’organisation. Enfin, j’ai démontré que la microcompartimentation de NarGHI aux pôles des cellules augmente le flux d’électrons et l’efficacité des chaines respiratoires associées à la respiration du nitrate.L’ensemble des travaux réalisés au cours de ma thèse permet une meilleure compréhension du processus de l’OXPHOS chez les procaryotes et donne une nouvelle vision des moyens employés pour optimiser l’OXPHOS en fonction des différentes conditions métaboliques. / By providing the energy for the cellular metabolism, oxidative phosphorylation (OXPHOS) is an essential process for most living organisms. In order to thrive, the efficiency of membrane respiratory chains which constitute the OXPHOS must be optimized. Thus it is important to address mechanisms by which the efficiency of the OXPHOS is regulated in response to varying metabolic needs.The question addressed during this PhD is the following: does it exist a specific organization of the OXPHOS components in prokaryotic membranes and does it contribute to the regulation of the OXPHOS process?I have investigated the spatio-temporal organization of a respiratory complex, the nitrate reductase NarGHI of the E. coli bacterium. After creating the tools needed to visualize submicrometrically this complex in the unique cell, I have shown the existence of a polar microcompartimentation during anaerobic respiration using fluorescence microscopy. I have demonstrated the dynamic subcellular organization of NarGHI in response to metabolic conditions. Anaerobiosis and a sufficient ∆pH are cues required to promote such cellular organization. Finally, I have demonstrated that polar microcompartimentation of the complex increases the electron flux and the efficiency of the associated respiratory chains.Overall, these results provide a novel view on OXPHOS in bacterial cells by demonstrating that spatio-temporal organization of a respiratory complex tunes the overall efficiency of the process in response to environmental cues.