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

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

Research output: Contribution to journalArticlepeer-review

122 Scopus citations


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.

Original languageEnglish (US)
Article numberddr395
Pages (from-to)4605-4616
Number of pages12
JournalHuman molecular genetics
Issue number23
StatePublished - Dec 2011
Externally publishedYes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology


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