Abstract
Metabolic reprogramming universally occurs in cancer. Mitochondria act as the hubs of bioenergetics and metabolism. The morphodynamics of mitochondria, comprised of fusion and fission processes, are closely associated with mitochondrial functions and are often dysregulated in cancer. In this study, we aim to investigate the mitochondrial morphodynamics and its functional consequences in human liver cancer. We observed excessive activation of mitochondrial fusion in tumor tissues from hepatocellular carcinoma (HCC) patients and in vitro cultured tumor organoids from cholangiocarcinoma (CCA). The knockdown of the fusion regulator genes, OPA1 (Optic atrophy 1) or MFN1 (Mitofusin 1), inhibited the fusion process in HCC cell lines and CCA tumor organoids. This resulted in inhibition of cell growth in vitro and tumor formation in vivo, after tumor cell engraftment in mice. This inhibitory effect is associated with the induction of cell apoptosis, but not related to cell cycle arrest. Genome-wide transcriptomic profiling revealed that the inhibition of fusion predominately affected cellular metabolic pathways. This was further confirmed by the blocking of mitochondrial fusion which attenuated oxygen consumption and cellular ATP production of tumor cells. In conclusion, increased mitochondrial fusion in liver cancer alters metabolism and fuels tumor cell growth.
Highlights
Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), is one of the leading causes of cancer related death
We further examined mitochondrial morphology in paired HCC and adjacent tissue derived from an HBV positive patient by electron microscopy
To investigate the clinical and functional relevance of mitochondrial morphodynamics in liver cancer, we examined key fusion proteins involved in mitochondrial dynamics
Summary
Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), is one of the leading causes of cancer related death. This is mainly attributed to the global prevalence of hepatitis virus infections and the rising prevalence of non-alcoholic fatty liver disease [1]. The research of cancer metabolism has largely extended our understanding of cancer biology and provided opportunities for therapeutic development [3]. A hallmark of cancer, is critical for the tumor initiation and development [5]. In addition to mitochondrial energetic metabolism transitions, the morphology of mitochondria is dynamic in cancer [6,7].
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