Focus: mitochondrial DNA mutations regulate metastasis of human breast cancer cells

Focus: mitochondrial DNA mutations regulate metastasis of human breast cancer cells

Mutations in mitochondrial DNA (mtDNA) might contribute to expression of the tumor phenotypes, such as metastatic potential, as well as to aging phenotypes and to clinical phenotypes of mitochondrial diseases by induction of mitochondrial respiration defects and the resultant overproduction of reactive oxygen species (ROS). To test whether mtDNA mutations mediate metastatic pathways in highly metastatic human tumor cells, we used human breast carcinoma MDA-MB-231 cells, which simultaneously expressed a highly metastatic potential, mitochondrial respiration defects, and ROS overproduction. Since mitochondrial respiratory function is controlled by both mtDNA and nuclear DNA, it is possible that nuclear DNA mutations contribute to the mitochondrial respiration defects and the highly metastatic potential found in MDA-MB-231 cells. To examine this possibility, we carried out mtDNA replacement of MDA-MB-231 cells by normal human mtDNA. For the complete mtDNA replacement, first we isolated mtDNA-less (ρ(0)) MDA-MB-231 cells, and then introduced normal human mtDNA into the ρ(0) MDA-MB-231 cells, and isolated trans-mitochondrial cells (cybrids) carrying nuclear DNA from MDA-MB-231 cells and mtDNA from a normal subject. The normal mtDNA transfer simultaneously induced restoration of mitochondrial respiratory function and suppression of the highly metastatic potential expressed in MDA-MB-231 cells, but did not suppress ROS overproduction. These observations suggest that mitochondrial respiration defects observed in MDA-MB-231 cells are caused by mutations in mtDNA but not in nuclear DNA, and are responsible for expression of the high metastatic potential without using ROS-mediated pathways. Thus, human tumor cells possess an mtDNA-mediated metastatic pathway that is required for expression of the highly metastatic potential in the absence of ROS production.

Source: Mitochondrial DNA mutations regulate metastasis of human breast cancer cells. Imanishi H, Hattori K, Wada R, Ishikawa K, Fukuda S, Takenaga K, Nakada K, Hayashi J. PLoS One. 2011;6(8):e23401.

Free paper available at: http://www.plosone.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0023401&representation=PDF

Les mutations dans l'ADN mitochondrial (ADNmt) pourraient contribuer à l'expression des phénotypes tumoraux, tels que le potentiel métastatique. Pour tester si les mutations de l'ADNmt peuvent médier des voies métastatique dans des cellules tumorales humaines hautement métastatiques, nous avons utilisé des cellules de carcinome mammaire humain MDA-MB-231. Nous avons effectué le remplacement de l’ADNmt des cellules MDA-MB-231 par de l'ADN mitochondrial humain normal. Le transfert d’ADNmt normal a induit simultanément la restauration de la fonction respiratoire mitochondriale, affectée dans les cellules MDA-MB-231, mais aussi la suppression du potentiel hautement métastatique exprimé par ces cellules. Ces observations suggèrent que les défauts observés dans la respiration mitochondriale des cellules MDA-MB-231 sont causés par des mutations de l'ADNmt, mais pas dans l'ADN nucléaire, et sont responsables de l'expression du potentiel métastatique élevé de ces cellules. Ainsi, les cellules tumorales humaines possèdent une voie médiée par l'ADNmt qui est requis pour l'expression du potentiel hautement métastatique.

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http://www.plosone.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0023401&representation=PDF