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

Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Human Molecular Genetics (Impact Factor: 6.39). 09/2011; 20(23):4605-16. DOI: 10.1093/hmg/ddr395
Source: PubMed


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.

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Available from: Lokendra K Sharma
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    • "Moderate increases in ROS can activate HIF-1α by oxidation of certain cysteine residues in HIF-1α regulatory proteins, whereas further oxidation of other residues at higher ROS levels inactivates HIF-1α and induces apoptosis (Page et al 2008; Wang et al 2012). In line with this, certain mutations in the ubiquinone-binding sites of complex I and complex II have been demonstrated to induce a pseudo-hypoxic metabolic switch from mitochondrial respiration towards glycolytic ATP production through activation of the Akt/HIF-1α pathway and down-regulation of activated AMPK in a ROS dose dependent manner (Guzy et al 2008; Sharma et al 2011). Thus, during chronic cell stress, lack of mitochondrial NAD + to sustain activation of the AMPK/PGC-1α/FOXO3a axis, and/or activation of the mTOR/HIF-1α axis at increasing ROS levels may shift the cell from mitochondrial respiration and active repair responses towards a more glycolytic metabolism with compromised repair mechanisms. "
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    • "The inhibition of complex I in the electron transport chain (ETC) increases the generation of ROS, which can then inhibit the ETC in a vicious cycle (Choi, 2011; Fato et al., 2010). This mitochondrial dysfunction is associated with the physiopathology of Parkinson's disease, bipolar disorder, tumorigenesis and cancer progression and invasion, making the mitochondria an important therapeutic target (Scola, Kim, Young, & Andreazza, 2013; Sharma et al., 2011; Smith, Hartley, Cochemé, & Murphy, 2012; Subramaniam & Chesselet, 2013; Taddei et al., 2012). Some phenolic compounds can restore mitochondrial dysfunction, suggesting a possible new therapeutic role for dietary polyphenols (Carrasco-Pozo, Gotteland, & Speisky, 2011; Carrasco-Pozo, Mizgier, Speisky, & Gotteland, 2012; Xie, Zhao, & Shen, 2012a, 2012b). "
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    • "Defective OXPHOS complexes , linked with mutations of mitochondrial DNA, were found in many other human malignancies. Deficiency of the Complex-I of the mitochondrial respiratory chain, associated with enhanced production of reactive oxygen species (Sharma et al. 2011), has been observed in human gastric cancer tissue (Puurand et al. 2012), renal and thyroid oncocytomas (Bonora et al. 2006; Simonnet et al. 2003). Some literature data suggests that NB cells are deficient in Complex-II activity, since mutations in genes encoding the subunits of the mitochondrial succinate dehydrogenase (SDH) complex have been shown in these malignancies (Cascon et al. 2008; Schimke et al. 2010). "
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