Nonsense and missense mutation of mitochondrial ND6 gene promotes cell migration and invasion in human lung adenocarcinoma

Abstract

BackgroundPrevious study showed that mitochondrial ND6 (mitND6) gene missense mutation resulted in NADH dehydrogenase deficiency and was associated with tumor metastasis in several mouse tumor cell lines. In the present study, we investigated the possible role of mitND6 gene nonsense and missense mutations in the metastasis of human lung adenocarcinoma.MethodsThe presence of mitND6 gene mutations was screened by DNA sequencing of tumor tissues from 87 primary lung adenocarcinoma patients and the correlation of the mutations with the clinical features was analyzed. In addition, we constructed cytoplasmic hybrid cells with denucleared primary lung adenocarcinoma cell as the mitochondria donor and mitochondria depleted lung adenocarcinoma A549 cell as the nuclear donor. Using these cells, we studied the effects of mitND6 gene nonsense and missense mutations on cell migration and invasion through wounding healing and matrigel-coated transwell assay. The effects of mitND6 gene mutations on NADH dehydrogenase activity and ROS production were analyzed by spectrophotometry and flow cytometry.ResultsmitND6 gene nonsense and missense mutations were detected in 11 of 87 lung adenocarcinoma specimens and was correlated with the clinical features including age, pathological grade, tumor stage, lymph node metastasis and survival rate. Moreover, A549 cell containing mitND6 gene nonsense and missense mutation exhibited significantly lower activity of NADH dehydrogenase, higher level of ROS, higher capacity of cell migration and invasion, and higher pAKT and pERK1/ERK2 expression level than cells with the wild type mitND6 gene. In addition, NADH dehydrogenase inhibitor rotenone was found to significantly promote the migration and invasion of A549 cells.ConclusionsOur data suggest that mitND6 gene nonsense and missense mutation might promote cell migration and invasion in lung adenocarcinoma, probably by NADH dehydrogenase deficiency induced over-production of ROS.

Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner

“…To date, there is no solid evidence implicating mutations in mtDNA as drivers of tumor formation; however, there are some nonrandom tumor progression-associated changes in mtDNA reported for some tumor types (26, 45, 46). Thus, mtDNA is more likely a contributor to controlling tumor latency or metastasis predicated on active mitochondrial-nuclear cross-talk.…”

Mitochondria and Mitochondrial ROS in Cancer: Novel Targets for Anticancer Therapy

“…Interestingly, the authors found that the ROS‐generating mtDNA mutations were not related to tumorigenicity in this study (Ishikawa et al, ). Similarly, cybrids containing mutant ND6 gene‐derived from primary lung adenocarcinoma cells exhibit lower complex I activity, higher ROS level, increased migration and invasion capacity (Yuan et al, ). However, in another study, this mutant mtDNA‐conferred metastatic potential was not associated with elevated ROS production (Imanishi et al, ), suggesting the involvement of other pathway(s) in metastasis regulation by mitochondria.…”

Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

“…ROS production appears to be a critical function of mitochondria, which do not need to be functionally intact to perform this role. Mutant mitochondrial proteins result in electron transport chain inefficiencies and excess ROS, yet they can promote migration and invasion . The fact that a dysfunctional electron transport chain may be beneficial to tumorigenesis suggests that it is the increased production of ROS and not ATP that makes these cells more aggressive.…”

“…Mutant mitochondrial proteins result in electron transport chain inefficiencies and excess ROS, yet they can promote migration and invasion. 39,40 The fact that a dysfunctional electron transport chain may be beneficial to tumorigenesis suggests that it is the increased production of ROS and not ATP that makes these cells more aggressive. Ishikawa et al demonstrated that transferring defective mitochondrial DNA from a highly metastatic tumor cell line to a poorly metastatic cell line caused less respiration, but increased ROS production and metastatic potential.…”