The role of the electron transport SDHC gene on lifespan and cancer.
Much attention has been focused on the hypothesis that oxidative damage plays in cellular and organismal aging. It is known that oxygen is initially converted to superoxide anion (O2-), one of reactive oxygen species (ROS), by electron leaked from mainly complex III in the electron transport system present in mitochondria, where it is the major endogenous source of ROS. We have shown that a mutation in a subunit, cytochrome b large subunit (SDHC), of complex II, also results in increasing O2- production and therefore lead to apoptosis and precocious aging in Caenorhabditis elegans. Recently, individuals with an inherited propensity for vascularized head and neck tumors (i.e., paragangliomas) have been demonstrated to contain one of several mutations in complex II. To further explore the role of oxidative stress from mitochondria on apoptosis and cancer, we established a transgenic cell line with a point mutation at the ubiquinone binding region in the SDHC gene. As expected, this mutation increased O2- production from complex II and led to excess apoptosis. Moreover, a significant fraction of the surviving cells from the apoptosis were transformed, as evidenced by increased tumor formation after injection into mice. Oxidative stress results in the damage to the cellular components including mitochondria and, therefore leads to apoptosis. Furthermore, oxidative stress must cause mutations in DNA and leads to cancer. It is suggested that oxidative stress from mitochondria play an important role of both apoptosis, which leads to precocious aging, and cancer.
Ishii
Naoaki
N
Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. nishii@is.icc.u-tokai.ac.jp
Ishii
Takamasa
T
Hartman
Philip S
PS
D000375:Aging / Q000502:physiology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D045303:Cytochromes b / Q000235:genetics; D042963:Electron Transport Complex II / Q000235:genetics*; D008136:Longevity / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000209:etiology; D018384:Oxidative Stress / Q000502:physiology*; D013385:Succinate Dehydrogenase / Q000235:genetics*; D019076:Transgenes
D029742:Caenorhabditis elegans Proteins; C472666:MEV-1 protein, C elegans; D008565:Membrane Proteins; C108096:SDHC protein, human; D045303:Cytochromes b; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase