The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

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

doi:10.1038/s41467-018-07922-3

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.

Highlights

Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during Mitochondria contain their own circular DNA (mtDNA) replication and transcription
As TOP1MT is strongly upregulated in a wide range of cancers, including colon and liver carcinomas, we investigated the impact of TOP1MT on carcinogenesis
We introduce the role of TOP1MT, the only topoisomerase exclusively localized to mitochondria[10,17], in carcinogenesis

Summary

Introduction

Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. 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. The cellular functions of mitochondria expand beyond energy production, encompassing redox homeostasis, promotion of cell death, and supply of biosynthetic metabolism[4,7,8] Based on their implication in multiple cellular functions, mitochondria empower cancer cell growth and survival in the pathological tumor microenvironment by ensuring biosynthetic and bioenergetics supply[6]. Our results reveal the importance of TOP1MT for tumor development and identify TOP1MT as a potential target for anticancer therapies

Methods

Results

Conclusion