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16 février 2021: 1 événement

  • Club Mitochondrie

    Mardi 16 février 11:30-12:30 - Nina Bonekamp - Max-Planck-Institut für Biologie des Alterns, Cologne Germany

    Inhibitors of mitochondrial transcription (IMTs) - novel chemical biology tools to manipulate mtDNA expression in vitro and in vivo

    Résumé : Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies, e.g. inborn errors of metabolism, neurodegeneration and cancer. We developed first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system. The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT causing IMT resistance. A cryo-EM structure of POLRMT with bound IMT further defined the allosteric binding site near the active centre cleft of POLRMT. Cancer cell growth and persistence of therapy-resistant cancer stem cells is reported to depend on OXPHOS and we therefore investigated anti-tumour effects of the IMTs. Four weeks of per oral IMT treatment is well tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues despite inducing a strong anti-tumour response in human cancer xenografts. In summary, the IMTs provide a potent and specific chemical biology tool to study the role for mtDNA expression in physiology and disease.

    En savoir plus : Club Mitochondrie