The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

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. Huang; J. U. Marquardt; Y. Pommier

doi:10.1038/s41467-018-07922-3

The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

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. Huang, J. U. Marquardt, Y. Pommier^*

^*Corresponding author for this work

Clinic of Internal Medicine I

41 Citations (Scopus)

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.

Original language	English
Article number	83
Journal	Nature Communications
Volume	10
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-018-07922-3
Publication status	Published - 01.12.2019

Funding

We are grateful to Langston Lim (Confocal Microscopy Core Facility, CCR, NCI, NIH) for support with confocal microscopy analyses; the CCR sequencing facility for their help in RNA sequencing; the CCR Genomics Core for their help with Nanostring analysis; Drs. Kunio Nagashima and Ulrich Baxa for electron microscopy support; Drs. Jennifer Dwyer and Shelley Hoover for scanning IHC slides; and the NHLBI/NIH DNA Sequencing and Computational Biology core for mitoRCA-seq analysis. Our studies are supported by the Center for Cancer Research, the intramural program of the National Cancer Institute (BC 006150).

Research Areas and Centers

Research Area: Luebeck Integrated Oncology Network (LION)

DFG Research Classification Scheme

2.22-14 Hematology, Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-018-07922-3

Cite this

Baechler, S. A., Factor, V. M., Dalla Rosa, I., Ravji, A., Becker, D., Khiati, S., Miller Jenkins, L. M., Lang, M., Sourbier, C., Michaels, S. A., Neckers, L. M., Zhang, H. L., Spinazzola, A., Huang, S. N., Marquardt, J. U., & Pommier, Y. (2019). The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis. Nature Communications, 10(1), Article 83. https://doi.org/10.1038/s41467-018-07922-3

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title = "The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis",

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.",

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Baechler, SA, Factor, VM, Dalla Rosa, I, Ravji, A, Becker, D, Khiati, S, Miller Jenkins, LM, Lang, M, Sourbier, C, Michaels, SA, Neckers, LM, Zhang, HL, Spinazzola, A, Huang, SN, Marquardt, JU & Pommier, Y 2019, 'The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis', Nature Communications, vol. 10, no. 1, 83. https://doi.org/10.1038/s41467-018-07922-3

TY - JOUR

T1 - The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

AU - Baechler, S. A.

AU - Factor, V. M.

AU - Dalla Rosa, I.

AU - Ravji, A.

AU - Becker, D.

AU - Khiati, S.

AU - Miller Jenkins, L. M.

AU - Lang, M.

AU - Sourbier, C.

AU - Michaels, S. A.

AU - Neckers, L. M.

AU - Zhang, H. L.

AU - Spinazzola, A.

AU - Huang, S. N.

AU - Marquardt, J. U.

AU - Pommier, Y.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

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Fingerprint

Dissecting the heterogeneity of tumor-initiating cells in hepatobiliary cancers: molecular characterization and targeting of stemness features

Cite this

The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Dissecting the heterogeneity of tumor-initiating cells in hepatobiliary cancers: molecular characterization and targeting of stemness features

Cite this