We recently identified a novel progeroid syndrome that we called MADaM (Mandibuloacral dysplasia associated to MTX2) with clinical features resembling Hutchinson-Gilford Progeria (HGPS), due to recessive null mutations in MTX2 encoding Metaxin 2 (MTX2), an outer mitochondrial membrane protein (Elouej et al., Nat Commun, 2020, PMID 32917887).
In this initial work, we showed that loss of MTX2 in patients’ primary fibroblasts leads to loss of its membrane partner Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Importantly, patients’ fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced cell proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. This work thus revealed an unsuspected pathophysiological link between mitochondrial composition and function and nuclear morphology.
In this research project, under the supervision of A. De Sandre-Giovanolli (MD-PhD) and A. Badache (PhD), we wish to deepen our understanding of the mechanistic basis of MADaM Syndrome, establish its probable links with HGPS in terms of dysregulated signaling pathways, and identify potential therapeutic strategies for patients. To this end, a combination of cell biology (including cell imaging), molecular biology and targeted proteomics approaches will be used, aiming to determine the respective roles of MTX1 and MTX2 in apoptosis resistance in a physiological and pathological context, identify if/which part of the mechanical connection between the mitochondria and nuclei is deficient and explore other, possibly causative, dysregulated cellular functions in cellular and/or animal models.
About Marseille Medical Genetics
Located at the heart of the third largest European university hospital center, Marseille Medical Genetics (MMG) boasts a triple mission: decipher the mechanisms involved in genetic diseases, open new diagnostic and therapeutic pathways and improve the quality of life of patients affected by these rare diseases. The MMG explores all facets of the discipline through a translational approach that focuses on the patient. Within the teams, researchers, clinicians, engineers, post docs and students seek to improve our knowledge of these diseases by combining the exploration of patient cohorts and pathophysiological models using state-of-the-art technologies.
Master’s degree in molecular/cellular biology or biomedical sciences, with a solid background in cell biology.
- Wet laboratory and analytical skills. Experience in cell culture, nucleic-acids and protein characterization (including immunoprecipitation, western blotting, basic cloning), RNAi and/or confocal microscopy will be considered as strong assets
- Rigor, perseverance. Critical thinking and problem solving skills are essential.
- Ability to work autonomously and as a team player.
- Detailed CV+ Cover Letter
- Contacts of two references
- Master's transcripts