Small-molecule inhibitors of human mitochondrial DNA transcription

2020 | journal article; research paper

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​Small-molecule inhibitors of human mitochondrial DNA transcription​
Bonekamp, N. A.; Peter, B.; Hillen, H. S. ; Felser, A.; Bergbrede, T.; Choidas, A. & Horn, M. et al.​ (2020) 
Nature588(7839) pp. 712-716​-716​.​ DOI: https://doi.org/10.1038/s41586-020-03048-z 

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Authors
Bonekamp, Nina A.; Peter, Bradley; Hillen, Hauke S. ; Felser, Andrea; Bergbrede, Tim; Choidas, Axel; Horn, Moritz; Unger, Anke; Di Lucrezia, Raffaella; Atanassov, Ilian; Li, Xinping; Koch, Uwe; Menninger, Sascha; Boros, Joanna; Habenberger, Peter; Giavalisco, Patrick; Cramer, Patrick ; Denzel, Martin S.; Nussbaumer, Peter; Klebl, Bert; Falkenberg, Maria; Gustafsson, Claes M.; Larsson, Nils-Göran
Abstract
Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe 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) system1-6. 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 that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7-17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease.
Issue Date
2020
Journal
Nature 
Project
EXC 2067: Multiscale Bioimaging 
FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala 
FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane 
Working Group
RG Cramer 
RG Hillen (Structure and Function of Molecular Machines) 
ISSN
0028-0836
eISSN
1476-4687
Language
English

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