Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

Abstract

It has been hypothesized that respiration defects caused by accumulation of pathogenicmitochondrial DNA (mtDNA) mutations and the resultant overproduction of reactive oxygen species (ROS) or lactates are responsible for aging and age-associated disorders, including diabetes and tumor development. However, there is no direct evidence to prove the involvement of mtDNA mutations in these processes, because it is difficult to exclude the possible involvement of nuclear DNA mutations. Our previous studies resolved this issue by using an mtDNA exchange technology and showed that a G13997A mtDNA mutation found in mouse tumor cells induces metastasis via ROS overproduction. Here, using transmitochondrial mice (mitomice), which we had generated previously by introducing G13997A mtDNAfrommouse tumor cells intomouseembryonic stemcells,we provide convincing evidence supporting part of the abovementioned hypothesis by showing that G13997A mtDNA regulates diabetes development, lymphoma formation, and metastasis - but not aging - in this model.