1. Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation.
- Author
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Sharma LK, Fang H, Liu J, Vartak R, Deng J, and Bai Y
- Subjects
- Antioxidants pharmacology, Cell Line, Tumor, Cell Transformation, Neoplastic drug effects, Electron Transport Complex I antagonists & inhibitors, Enzyme Activation drug effects, Humans, Mitochondria drug effects, Oxidation-Reduction drug effects, Oxidative Stress drug effects, Saccharomyces cerevisiae drug effects, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins metabolism, Signal Transduction drug effects, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Electron Transport Complex I metabolism, Mitochondria metabolism, Proto-Oncogene Proteins c-akt metabolism, Reactive Oxygen Species metabolism
- Abstract
Previously, we have shown that a heteroplasmic mutation in mitochondrial DNA-encoded complex I ND5 subunit gene resulted in an enhanced tumorigenesis through increased resistance to apoptosis. Here we report that the tumorigenic phenotype associated with complex I dysfunction could be reversed by introducing a yeast NADH quinone oxidoreductase (NDI1) gene. The NDI1 mediated electron transfer from NADH to Co-Q, bypassed the defective complex I and restored oxidative phosphorylation in the host cells. Alternatively, suppression of complex I activity by a specific inhibitor, rotenone or induction of oxidative stress by paraquat led to an increase in the phosphorylation of v-AKT murine thymoma viral oncogene (AKT) and enhanced the tumorigenesis. On the other hand, antioxidant treatment can ameliorate the reactive oxygen species-mediated AKT activation and reverse the tumorigenicity of complex I-deficient cells. Our results suggest that complex I defects could promote tumorigenesis through induction of oxidative stress and activation of AKT pathway.
- Published
- 2011
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