Abstract
Mitochondrial reactive oxygen species (ROS) which are mainly generated as an uncoupled consequence of electron transport cause the cellular and organismal oxidative stress. It has been previously demonstrated that the excessive mitochondrial ROS production caused by mitochondrial complex II SDHC mutation results in premature death in C. elegans mev-1 mutant (G71E) and D. melanogaster mev-1-mimic transgenic flies (I71E), and excessive apoptosis and tumorigenesis in mouse embryonic fibroblast SDHC E69 cells (V69E) (M. Tsuda, et al. BBRC 2007, T. Ishii, et al. Cancer Res. 2005, N. Ishii, et al. Nature 1998). In humans, it has been reported that some mutations in SDHB, SDHC or SDHD often result in hereditary and/or sporadic paragangliomas, gastrointestinal stromal tumors and pheochromocytomas (T. Ishii, et al. BBA 2013). Recently, Tet-mev-1 conditional transgenic mice have been established using our uniquely developed Tet-On/Off system, which can induce the mutated SDHC (V69E) coding gene to be equally and competitively expressed compared to the endogenous wild-type SDHC gene. The Tet-mev-1 mice experienced intracellular oxidative stress by mitochondrial respiratory chain dysfunction developed low birth weight, growth retardation, age-dependent corneal pathophysiological changes, low fertility, recurrent miscarriage and age-dependently disrupted memory consolidation with astrocyte defects (T. Ishii, et al. Mitochondrion 2011; H. Onouchi, et al. IOVS 2012; Y. Uchino, et al. PLoS ONE 2012; T. Ishii, et al. Redox Biology 2014; T. Ishii, et al. Aging Cell 2016) Here, it has been demonstrated that lymphocyte accumulation which is chronically activated with age influences the anti-carcinogenesis of large-cell lung carcinoma with oxidative stress in Tet-mev-1 mice. In aged Tet-mev-1 mice, large-cell neoplastic cells were developed into the lymphocyte accumulation in lung. The lymphocytes which were associated with γδT cell activation leading to innate immune responses were initiated by ω-6 fatty acid peroxidation-derived 4-hydroxy-2-nonenal (4-HNE). We propose that the 4-HNE-induced innate immune responses which associate with γδT cells involved in intraepithelial lymphocytes (IELs) may initially prohibit the oxidative stress-developed carcinoma.