Journal Article

Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation

Lokendra Kumar Sharma, Hezhi Fang, Jiangtao Liu, Rasika Vartak, Janice Deng and Yidong Bai

in Human Molecular Genetics

Volume 20, issue 23, pages 4605-4616
Published in print December 2011 | ISSN: 0964-6906
Published online September 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr395
Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation

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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.

Journal Article.  6476 words.  Illustrated.

Subjects: Genetics and Genomics

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