Abstract/Summary

Cancer metastasis is responsible for 90% of cancer deaths. It is well known that metabolic reprogramming, which is one of the hallmarks of cancer, plays an important role in increasing cancer cell migration and metastasis. Changes in mitochondrial morphology are thought to affect their function; however the mechanism is still unclear. Moreover, it is not known whether changes in mitochondrial morphology and their metabolism can affect cell migration or not. The overall aim of this study was to investigate the link between mitochondrial morphology and their metabolism with cancer cell migration. Several factors such as different glucose levels, PGC-1α activator, hydrogen peroxide, and anti-metabolic agents that can affect mitochondrial morphology has been used to investigate the effect of mitochondrial morphologic changes on their metabolism and cell migration. Furthermore, p66shc and TRAP1, the function of which are related to mitochondria, have been identified as novel components related to reprogramming metabolism and cell migration. Using confocal and time-lapse microscopy, as well as through measuring ATP production, lactate production, and estimation of ROS generation in MDA-MB-231 breast cancer cells, HT1080 fibrosarcoma cells, and HeLa cells. This study has been found that mitochondria fragmentation induces metabolic reprogramming from oxidative phosphorylation to glycolysis, due to reducing mitochondrial inner membrane surface area which required for mitochondrial oxidative phosphorylation enzyme activity, which in turn led to increases in cancer cell migration. Inhibition of mitochondrial fragmentation using a mitochondrial division-1 inhibitor has led to significant decreases in glycolysis and cell migration. This study has also shown that the function of pro-apoptotic p66shc and cytoprotective TRAP1 are correlated strongly to each other. Increasing the expression of p66shc can trigger metabolic reprogramming and enhance cancer cell migration, whereas, increasing TRAP1 expression inhibits apoptosis, which can be induced by activated p66shc. In conclusion, mitochondrial fragmentation can alter cancer cell metabolism to glycolysis and activated p66shc is a main cause of this metabolic reprogramming, which controls cancer cell migration. In addition, TRAP1 and mitochondrial fragmentation can increase resistance to apoptosis induced by oxidative stress. This finding could be exploited in the development of new therapy for cancer treatment.