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Small-molecule inhibitors of human mitochondrial DNA transcription

Author

Listed:
  • 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
    Acus Laboratories
    JLP Health)

  • 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
    Karolinska Institutet
    Karolinska Institutet)

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.

Suggested Citation

  • 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 Men, 2020. "Small-molecule inhibitors of human mitochondrial DNA transcription," Nature, Nature, vol. 588(7839), pages 712-716, December.
  • Handle: RePEc:nat:nature:v:588:y:2020:i:7839:d:10.1038_s41586-020-03048-z
    DOI: 10.1038/s41586-020-03048-z
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    Citations

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    Cited by:

    1. Kangqiang Qiu & Weiwei Zou & Hongbao Fang & Mingang Hao & Kritika Mehta & Zhiqi Tian & Jun-Lin Guan & Kai Zhang & Taosheng Huang & Jiajie Diao, 2022. "Light-activated mitochondrial fission through optogenetic control of mitochondria-lysosome contacts," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    2. Shane T. Killarney & Rachel Washart & Ryan S. Soderquist & Jacob P. Hoj & Jamie Lebhar & Kevin H. Lin & Kris C. Wood, 2023. "Executioner caspases restrict mitochondrial RNA-driven Type I IFN induction during chemotherapy-induced apoptosis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Sarah Rösing & Fabian Ullrich & Susann Meisterfeld & Franziska Schmidt & Laura Mlitzko & Marijana Croon & Ryan G Nattrass & Nadia Eberl & Julia Mahlberg & Martin Schlee & Anja Wieland & Philipp Simon , 2024. "Chronic endoplasmic reticulum stress in myotonic dystrophy type 2 promotes autoimmunity via mitochondrial DNA release," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Vanessa López-Polo & Mate Maus & Emmanouil Zacharioudakis & Miguel Lafarga & Camille Stephan-Otto Attolini & Francisco D. M. Marques & Marta Kovatcheva & Evripidis Gavathiotis & Manuel Serrano, 2024. "Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Karl Herbine & Ashok R. Nayak & Dmitry Temiakov, 2024. "Structural basis for substrate binding and selection by human mitochondrial RNA polymerase," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    6. Yujie Zhu & Mingchao Zhang & Weiran Wang & Shuang Qu & Minghui Liu & Weiwei Rong & Wenwen Yang & Hongwei Liang & Caihong Zeng & Xiaodong Zhu & Limin Li & Zhihong Liu & Ke Zen, 2023. "Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Abhishek Aich & Angela Boshnakovska & Steffen Witte & Tanja Gall & Kerstin Unthan-Fechner & Roya Yousefi & Arpita Chowdhury & Drishan Dahal & Aditi Methi & Svenja Kaufmann & Ivan Silbern & Jan Prochaz, 2024. "Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    8. Yanan Li & Yonghua Wu & Ru Xu & Jialing Guo & Fenglei Quan & Yongyuan Zhang & Di Huang & Yiran Pei & Hua Gao & Wei Liu & Junjie Liu & Zhenzhong Zhang & Ruijie Deng & Jinjin Shi & Kaixiang Zhang, 2023. "In vivo imaging of mitochondrial DNA mutations using an integrated nano Cas12a sensor," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    9. Naijun Miao & Zhuning Wang & Qinlan Wang & Hongyan Xie & Ninghao Yang & Yanzhe Wang & Jin Wang & Haixia Kang & Wenjuan Bai & Yuanyuan Wang & Rui He & Kepeng Yan & Yang Wang & Qiongyi Hu & Zhaoyuan Liu, 2023. "Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    10. Bingjie Guan & Youdong Liu & Bowen Xie & Senlin Zhao & Abudushalamu Yalikun & Weiwei Chen & Menghua Zhou & Qi Gu & Dongwang Yan, 2024. "Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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