Regulation of metastasis; mitochondrial DNA mutations have appeared on stage.

It has been controversial whether mtDNA mutations are responsible for tumorigenesis and for the process to develop metastases. To clarify this issue, we established trans-mitochondrial cybrids with mtDNA exchanged between mouse tumor cells that possess high and low metastatic potential. The results revealed that the G13997A mutation in the ND6 gene of mtDNA from highly metastatic tumor cells reversibly controlled development of metastases by overproduction of reactive oxygen species (ROS). The transmitochondrial model mice possessing G13997A mtDNA showed symptoms of impaired glucose tolerability, suggesting that ROS generated mtDNA mutations can regulate not only metastatic potential, but also age-associated disorders such as diabetes. We also identified other mtDNA mutations that affect metastatic potential but the mechanisms are independent of ROS production. The mtDNA-mediated reversible control of metastasis and age-associated disorders are novel functions of mtDNA, and suggests that ROS scavengers may be therapeutically effective to suppress these phenotypes.