Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth

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.

The biological process of lysine‐tRNA charging is therapeutically targetable in liver cancer

“…We have included three batches of healthy human liver organoids and three batches of CC organoids. Because organoids are very difficult to be cultured from HCC tissues, we used liver tumour organoids cultured from CC patients, 18 of which the KARS1 expression levels were shown in Figure 6A. Importantly, similar to what we found in HCC patients, KARS1 expression was significantly higher in patient CC tumour tissues based on the GEPIA database.…”

Comprehensive in silico analysis for identification of novel candidate target genes, including DHX36, OPA1, and SENP2, located on chromosome 3q in head and neck cancers

“…70 Its overexpression was detected in various tumors including lung cancer 71 and hepatocellular carcinoma. 72 In addition, resistance to chemotherapeutic reagents was demonstrated to be partly stemming from deregulation of OPA1 processing that causes resistance to apoptosis. 73 Our results also suggest OPA1 as a potential oncogene considering its overexpression in HNSC samples.…”

“…Apart from its role associated with mitochondria, OPA1 has been reported to modulate apoptosis via controlling cristae junction remodeling, 68,69 to regulate mitochondrial respiration, and mitochondria‐associated cell proliferation 70 . Its overexpression was detected in various tumors including lung cancer 71 and hepatocellular carcinoma 72 . In addition, resistance to chemotherapeutic reagents was demonstrated to be partly stemming from deregulation of OPA1 processing that causes resistance to apoptosis 73 .…”

“The Loss of Golden Touch”: Mitochondria-Organelle Interactions, Metabolism, and Cancer

“…Of note, in vitro experiments indicated that MFN1 depletion reprogramed glucose metabolism, eliciting aerobic glycolysis instead of Oxphos. Contrasting results were collected by Li et al, who observed excessive mitochondrial fusion in the tumor tissues of human HCC and in vitro cultured tumor organoids from cholangiocarcinoma [ 41 ]. The knockdown of both MFN1 and OPA1 inhibited mitochondrial fusion in both experimental settings, leading to a reduced cell growth and tumor formation.…”

“…The knockdown of both MFN1 and OPA1 inhibited mitochondrial fusion in both experimental settings, leading to a reduced cell growth and tumor formation. The authors ascribed the antitumor effect of OPA1 and MFN1 silencing to the induction of pro-apoptotic mechanisms, inhibition of oxidative metabolism, and ATP production [ 41 ]. A realistic speculation might be that the apparently inconsistent observations could be due to the different experimental settings used in these studies.…”