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The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

Author

Listed:
  • S. A. Baechler

    (National Cancer Institute)

  • V. M. Factor

    (National Cancer Institute)

  • I. Dalla Rosa

    (University College London)

  • A. Ravji

    (National Cancer Institute)

  • D. Becker

    (Johannes Gutenberg University)

  • S. Khiati

    (Universite d’Angers)

  • L. M. Miller Jenkins

    (National Institutes of Health)

  • M. Lang

    (National Institutes of Health)

  • C. Sourbier

    (National Institutes of Health
    U.S. Food and Drug Administration)

  • S. A. Michaels

    (National Cancer Institute)

  • L. M. Neckers

    (National Institutes of Health)

  • H. L. Zhang

    (National Cancer Institute)

  • A. Spinazzola

    (University College London)

  • S. N. Huang

    (National Cancer Institute)

  • J. U. Marquardt

    (Johannes Gutenberg University)

  • Y. Pommier

    (National Cancer Institute)

Abstract

Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies.

Suggested Citation

  • S. A. Baechler & V. M. Factor & I. Dalla Rosa & A. Ravji & D. Becker & S. Khiati & L. M. Miller Jenkins & M. Lang & C. Sourbier & S. A. Michaels & L. M. Neckers & H. L. Zhang & A. Spinazzola & S. N. H, 2019. "The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07922-3
    DOI: 10.1038/s41467-018-07922-3
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    Cited by:

    1. Yilun Sun & Simone A. Baechler & Xiaohu Zhang & Suresh Kumar & Valentina M. Factor & Yasuhiro Arakawa & Cindy H. Chau & Kanako Okamoto & Anup Parikh & Bob Walker & Yijun P. Su & Jiji Chen & Tabitha Ti, 2023. "Targeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Peixiang Zhang & Joseph J. Munier & Carrie B. Wiese & Laurent Vergnes & Jenny C. Link & Fahim Abbasi & Emilio Ronquillo & Katherine Scheker & Antonio Muñoz & Yu-Lin Kuang & Elizabeth Theusch & Meng Lu, 2024. "X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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