Abstract
We have previously demonstrated that the excessive mitochondrial O2•- production caused by mitochondrial complex II SDHC mutations results in premature death in C. elegans and Drosophila and cancer in mouse embryonic fibroblast cells (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 mutations in SDHB, SDHC or SDHD often result in inherited head and neck paragangliomas (PGLs).
Recently, we established Tet-mev-1 conditional transgenic mice using our uniquely developed Tet-On/Off system, which can induce the mutated SDHC gene to be equally and competitively expressed compared to the endogenous wild-type SDHC gene (T. Ishii, et al. Mitochondrion 2011). These mice experienced mitochondrial respiratory chain dysfunction that resulted in O2•- overproduction. The oxidative stress caused excessive apoptosis leading to low birth weight and growth retardation in the neonatal developmental phase in Tet-mev-1 mice. Moreover Tet-mev-1 mice have low pregnancy and fertility rates, and occasionally result in maternal death. In an in vitro fertilization assay, the ovulation rate and sperm activity were slightly reduced, but early embryogenesis was not changed.
In this study, the results suggest that SDHC V69E mutation might significantly affect some roles at the time of implantation or placental functions. We hypothesize that the mutation causes not only excessive O2•- production by mitochondrial respiratory chain abnormality but also mimic-hypoxic condition by HIF-induced signal transductions leading to infertility, habitual abortion and maternal death.
