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^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Medizinische Klinik I

43 Zitate (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.

Originalsprache	Englisch
Aufsatznummer	83
Zeitschrift	Nature Communications
Jahrgang	10
Ausgabenummer	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-018-07922-3
Publikationsstatus	Veröffentlicht - 01.12.2019

Fördermittel

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).

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Profilbereich: Lübeck Integrated Oncology Network (LION)

DFG-Fachsystematik

2.22-14 Hämatologie, Onkologie

Dokumente

10.1038/s41467-018-07922-3

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Link to publication in Scopus

Analyse der Heterogenität von Tumor-initiierenden Zellen in Hepato-biliären Tumoren - Molekulare Charakterisierung und therapeutisches Abzielen auf (Krebs-)Stammzell-Eigenschaften
Marquardt, J. (Projektleiter*in (PI))
01.01.12 → 31.12.20
Projekt: DFG Einzelprojekte › DFG Einzelförderungen (Sachbeihilfen)

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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), Artikel 83. https://doi.org/10.1038/s41467-018-07922-3

@article{493d0664d967445bae56df14b8904144,

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.",

author = "Baechler, \{S. A.\} and Factor, \{V. M.\} and \{Dalla Rosa\}, I. and A. Ravji and D. Becker and S. Khiati and \{Miller Jenkins\}, \{L. M.\} and M. Lang and C. Sourbier and Michaels, \{S. A.\} and Neckers, \{L. M.\} and Zhang, \{H. L.\} and A. Spinazzola and Huang, \{S. N.\} and Marquardt, \{J. U.\} and Y. Pommier",

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year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-018-07922-3",

language = "English",

volume = "10",

journal = "Nature Communications",

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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, Jg. 10, Nr. 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.

UR - https://www.scopus.com/pages/publications/85059746321

U2 - 10.1038/s41467-018-07922-3

DO - 10.1038/s41467-018-07922-3

M3 - Journal articles

C2 - 30622257

AN - SCOPUS:85059746321

SN - 1751-8628

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 83

ER -

The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

Abstract

Fördermittel

UN SDGs

Strategische Forschungsbereiche und Zentren

DFG-Fachsystematik

Dokumente

Weitere Links

Fingerprint

Projekte

Analyse der Heterogenität von Tumor-initiierenden Zellen in Hepato-biliären Tumoren - Molekulare Charakterisierung und therapeutisches Abzielen auf (Krebs-)Stammzell-Eigenschaften

Zitieren