Résumé
Fifty percent of all patients with cancer worldwide require radiotherapy. Over the past decades, technical advances and progress in imaging have enabled more precise irradiation of the tumour, leading to a reduction in the volume of normal tissue irradiated, thanks to hadron therapy (using proton & carbon particles). However, the risk of sequelae after treatment for patients has not yet been completely eliminated. In the case of brain tumours, despite the improvement in the precision of radiation delivery with hadron therapy, studies have shown the modification of the function and structure of neurons after irradiation with protons in treated patients. The molecular pathways involved in generating these neurotoxic effects are not completely understood. Based on these data, we are analysing the impact of proton exposure on the nervous system by examining the effects on mitochondrial function, target of ionizing radiation potentially implicated in the occurrence of neurodegenerative diseases. To achieve this objective, the nematode Caenorhabditis elegans was micro-irradiated with 220 Gy of protons (4 MeV) in the nerve ring, where most of the neurons are located, using the proton microbeam, MIRCOM. Our results show that protons induce mitochondrial dysfunction characterized by an immediate dose-dependent loss of mitochondrial membrane potential (ΔΨm) associated with oxidative stress after 24 hours characterized by induction of the antioxidant proteins in the targeted region, observed using sod-1::GFP and sod-3::GFP strains. Moreover, we demonstrated a 2-fold increase in mtDNA copy number in the targeted region 24 h after irradiation. In addition, using GFP::LGG-1 strain an induction of mitophagy in the irradiated region was observed after 6 hours of irradiation associated with up-regulation of gene expression of pink-1 (PTEN-induced kinase) and pdr-1 (C. elegans parkin homolog). Furthermore, our data showed no significant change in the whole-body oxygen consumption after 24h of micro irradiating the nerve ring using Seahorse XF Analysers. These results indicate a global mitochondrial dysfunction. They will be completed by DNA damage and behavioural studies, enabling a better understanding of radiation-induced neurological effects and the identification of the biological pathways involved in the initiation and progression of side effects, in order to quantify their risk of occurrence and propose new therapies.