Targeting the complex I and III of mitochondrial electron transport chain as a potentially viable option in liver cancer management

Qin Yang,Wanlu Cao,Meng Li,Qiuwei Pan,Ling Wang,Jiaye Liu

doi:10.1038/s41420-021-00675-x

Abstract

Liver cancer is one of the most common and lethal types of oncological disease in the world, with limited treatment options. New treatment modalities are desperately needed, but their development is hampered by a lack of insight into the underlying molecular mechanisms of disease. It is clear that metabolic reprogramming in mitochondrial function is intimately linked to the liver cancer process, prompting the possibility to explore mitochondrial biochemistry as a potential therapeutic target. Here we report that depletion of mitochondrial DNA, pharmacologic inhibition of mitochondrial electron transport chain (mETC) complex I/complex III, or genetic of mETC complex I restricts cancer cell growth and clonogenicity in various preclinical models of liver cancer, including cell lines, mouse liver organoids, and murine xenografts. The restriction is linked to the production of reactive oxygen species, apoptosis induction and reduced ATP generation. As a result, our findings suggest that the mETC compartment of mitochondria could be a potential therapeutic target in liver cancer.

Highlights

Liver cancer, mainly consisting of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is the sixth most common cancer and one of the leading causes of cancer-related death [1]
These results suggested that the functionality of mitochondrial electron transport chain (mETC) complex I and mETC complex III was required for liver cancer cell survival
Increasing the understanding of liver cancer cell physiology may lead to novel therapeutic options, and the current study focused on the role of the mETC contributes to the increase

Summary

Introduction

Mainly consisting of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is the sixth most common cancer and one of the leading causes of cancer-related death [1]. Hepatitis B and C, as well as metabolic syndrome and type II diabetes, are all risk factors for HCC. The molecular details of disease progression and how these risk factors translate in cancer development are less clear, hampering rational efforts to develop new therapy. A greater understanding of the progression of liver cancer is urgently required. Hepatocytes are a unique cell type in many aspects, including the high abundance of mitochondria in their cytoplasm, which appear to be involved in the oncogenic transformation of this cell type [3]. The central role of mitochondria in hepatocyte metabolism has given rise to speculation that this organelle may provide novel therapeutic targets for liver cancer treatment, despite the fact that our understanding of its functionality in the HCC process is far from complete [5]

Methods

Results

Conclusion