The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis.
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
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.
Mitochondrial metabolic reprogramming: An important player in liver cancer progression.
Jin Tianqiang,Wang Chao,Tian Yu,Dai Chaoliu,Zhu Yuwen,Xu Feng
Mitochondria are known as essential biosynthetic, bioenergetic and signaling organelles, and play a critical role in cell differentiation, proliferation, and death. Nowadays, cancer is emergingly considered as a mitochondrial metabolic disease. Mitochondria also play an essential role in liver carcinogenesis. Liver cells are highly regenerative and require high energy. For that reason, a large number of mitochondria are present and functional in liver cells. Abnormalities in mitochondrial metabolism in human liver are known to be one of the carcinogenic factors. Interestingly, immune checkpoints regulate mitochondrial metabolic energetics of the tumor, the tumor microenvironment, as well as the tumor-specific immune response. This regulation forms a positive loop between the metabolic reprogramming of both cancer cells and immune cells. In this review, we discuss the evidence and mechanisms that mitochondria interplay with immune checkpoints to influence different steps of oncogenesis, as well as the potential of mitochondria as therapeutic targets for liver cancer therapy.