Abstract
Since Otto Warburg linked mitochondrial physiology and oncogenesis in the 1930s, a number of studies have focused on the analysis of the genetic basis for the presence of aerobic glycolysis in cancer cells. However, little or no evidence exists today to indicate that mtDNA mutations are directly responsible for the initiation of tumor onset. Based on a model of gliomagenesis in the mouse, we aimed to explore whether or not mtDNA mutations are associated with the initiation of tumor formation, maintenance and aggressiveness. We reproduced the different molecular events that lead from tumor initiation to progression in the mouse glioma. In human gliomas, most of the genetic alterations that have been previously identified result in the aberrant activation of different signaling pathways and deregulation of the cell cycle. Our data indicates that mitochondrial dysfunction is associated with reactive oxygen species (ROS) generation, leading to increased nuclear DNA (nDNA) mutagenesis, but maintaining the integrity of the mitochondrial genome. In addition, mutational stability has been observed in entire mtDNA of human gliomas; this is in full agreement with the results obtained in the cancer mouse model. We use this model as a paradigm of oncogenic transformation due to the fact that mutations commonly found in gliomas appear to be the most common molecular alterations leading to tumor development in most types of human cancer. Our results indicate that the mtDNA genome is kept by the cell as a “genetic sanctuary” during tumor development in the mouse and humans. This is compatible with the hypothesis that the mtDNA molecule plays an essential role in the control of the cellular adaptive survival response to tumor-induced oxidative stress. The integrity of mtDNA seems to be a necessary element for responding to the increased ROS production associated with the oncogenic process.
Highlights
Mitochondria are central to cell metabolism, being the principal energy source of the cell, thanks to the cytochrome enzymes of terminal electron transport and the enzymes of the citric acid cycle, fatty acid oxidation, and oxidative phosphorylation
Oncogene-induced reactive oxygen species (ROS) generation is associated with chromosomal instability
In order to examine the role of mitochondrial DNA (mtDNA) mutations in the development of tumor cells, four groups of primary astrocytes and two cell lines derived from tumors formed by primary astrocytes RbloxP/ loxP/RasV12 and cRb2/2/RasV12 in SCID mice (T653 and T731, respectively) were chosen (Table 1)
Summary
Mitochondria are central to cell metabolism, being the principal energy source of the cell, thanks to the cytochrome enzymes of terminal electron transport and the enzymes of the citric acid cycle, fatty acid oxidation, and oxidative phosphorylation. This energy is gradually converted into a proton gradient. A number of notable differences in the mitochondria of normal and cancer cells have been described These include differences in mitochondrial metabolic activity [6,7], the molecular composition of the mitochondria and the mitochondrial DNA (mtDNA) sequence [8,9], as well as alterations of nuclear genes that may affect mitochondrial function [10,11,12]
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