A mutation in the SDHC gene of complex II increases oxidative stress, resulting in apoptosis and tumorigenesis.
Intracellular oxidative stress from mitochondria is thought to be important in carcinogenesis and tumorigenesis, but direct experimental proof is limited. In this study, a transgenic mouse cell line (SDHC E69) with a mutated SDHC gene (a subunit of complex II in the electron transport chain) was constructed to test this question. The SDHC E69 cells overproduced superoxide anion (O(2)(-)) from mitochondria, had elevated cytoplasmic carbonyl proteins and 8-OH-deoxyguanine in their DNA as well as significantly higher mutation frequencies than wild type. There were many apoptotic cells in this cell line, as predicted by the observed increase in caspase 3 activity, decrease in mitochondrial membrane potential, and structural changes in their mitochondria. In addition, some cells that escaped from apoptosis underwent transformation, as evidenced by the fact that SDHC E69 cells caused benign tumors when injected under the epithelium of nude mice. These results underscore the notion that mitochondrially generated oxidative stress can contribute to nuclear DNA damage, mutagenesis, and ultimately, tumorigenesis.
Ishii
Takamasa
T
Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa, Japan.
Yasuda
Kayo
K
Akatsuka
Akira
A
Hino
Okio
O
Hartman
Philip S
PS
Ishii
Naoaki
N
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001426:Bacterial Proteins / Q000235:genetics; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003001:Cloning, Molecular; D017931:DNA Primers; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D005787:Gene Frequency; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D018384:Oxidative Stress / Q000502:physiology*; D016133:Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013385:Succinate Dehydrogenase / Q000235:genetics; D013481:Superoxides / Q000378:metabolism
D001426:Bacterial Proteins; D017931:DNA Primers; D008565:Membrane Proteins; C108096:SDHC protein, human; C486355:SdhC protein, bacteria; D013481:Superoxides; D000080242:8-Hydroxy-2'-Deoxyguanosine; D013385:Succinate Dehydrogenase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003849:Deoxyguanosine