Sharma LK, et al. (2011) Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum Mol Genet 20(23):4605-16
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.
|Status: Published||Type: Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov't||PubMed ID: 21890492|
Topics addressed in this paper
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