Small-molecule inhibitors of human mitochondrial DNA transcription

Nina A. Bonekamp, Bradley Peter, Hauke S. Hillen, Andrea Felser, Tim Bergbrede, Axel Choidas, Moritz Horn, Anke Unger, Raffaella Lucrezia, Ilian Atanassov, Xinping Li, Uwe Koch, Sascha Menninger, Joanna Boros, Peter Habenberger, Patrick Giavalisco, Patrick Cramer, Martin S. Denzel, Peter Nussbaumer, Bert Klebl, Maria Falkenberg, Claes M. Gustafsson () and Nils-Göran Larsson ()
Additional contact information
Nina A. Bonekamp: Max Planck Institute for Biology of Ageing
Bradley Peter: University of Gothenburg
Hauke S. Hillen: Max Planck Institute for Biophysical Chemistry
Andrea Felser: Karolinska Institutet
Tim Bergbrede: Lead Discovery Center
Axel Choidas: Lead Discovery Center
Moritz Horn: Max Planck Institute for Biology of Ageing
Anke Unger: Lead Discovery Center
Raffaella Lucrezia: Lead Discovery Center
Ilian Atanassov: Max Planck Institute for Biology of Ageing
Xinping Li: Max Planck Institute for Biology of Ageing
Uwe Koch: Lead Discovery Center
Sascha Menninger: Lead Discovery Center
Joanna Boros: Lead Discovery Center
Peter Habenberger: Lead Discovery Center
Patrick Giavalisco: Max Planck Institute for Biology of Ageing
Patrick Cramer: Max Planck Institute for Biophysical Chemistry
Martin S. Denzel: Max Planck Institute for Biology of Ageing
Peter Nussbaumer: Lead Discovery Center
Bert Klebl: Lead Discovery Center
Maria Falkenberg: University of Gothenburg
Claes M. Gustafsson: University of Gothenburg
Nils-Göran Larsson: Max Planck Institute for Biology of Ageing

Nature, 2020, vol. 588, issue 7839, 712-716

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-03048-z

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