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

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.

SUBMITTER: Sharma LK

PROVIDER: S-EPMC3209831 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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

Sharma Lokendra Kumar LK Fang Hezhi H Liu Jiangtao J Vartak Rasika R Deng Janice J Bai Yidong Y

Human molecular genetics 20110902 23

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 ce ...[more]

PMID: 21890492

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Project description:Akt, a serine/threonine kinase has been shown to stimulate glycolysis in cancer cells but its role in mitochondrial respiration is unknown. Using PTEN-knockout mouse embryonic fibroblasts (MEF(PTEN-/-)) with hyper-activated Akt as a cell model, we observed a higher respiratory capacity in MEF(PTEN-/-) compared to the wildtype (MEF(WT)). The respiratory phenotype observed in MEF(PTEN-/-) was reproduced in MEF(WT) by gene silencing of PTEN which substantiated its role in regulating mitochondrial function. The increased activities of the respiratory complexes (RCs) I, III and IV were retained in the same relative proportions as those present in MEF(WT), alluding to a possible co-ordinated regulation by PTEN/Akt. Using LY294002 (a PI3K inhibitor) and Akt inhibitor IV, we showed that the regulation of enzyme activities and protein expressions of the RCs was dependent on PI3K/Akt. There was insignificant difference in the protein expressions of mitochondrial transcription factor: peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and its downstream targets, the nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (mtTFA) between MEF(PTEN-/-) and MEF(WT). Similarly, mRNA levels of the same subunits of the RCs detected in Western blots were not significantly different between MEF(PTEN-/-) and MEF(WT) suggesting that the regulation by Akt on mitochondrial function was probably not via gene transcription. On the other hand, a decrease of total 4E-BP1 with a higher expression of its phosphorylated form relative to total 4E-BP1 was found in MEF(PTEN-/-), which inferred that the regulation of mitochondrial respiratory activities by Akt was in part through this protein translation pathway. Notably, gene silencing of 4E-BP1 up-regulated the protein expressions of all RCs and the action of 4E-BP1 appeared to be specific to these mitochondrial proteins. In conclusion, PTEN inactivation bestowed a bioenergetic advantage to the cells by up-regulating mitochondrial respiratory capacity through the 4E-BP1-mediated protein translation pathway.

Dataset Information

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

Publications

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

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