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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: 6.68). 09/2011; 20(23):4605-16. DOI: 10.1093/hmg/ddr395
Source: PubMed

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.

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Available from: Lokendra K Sharma, Aug 01, 2015
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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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    • "mutation ( Sharma et al . , 2011 ) . Furthermore , ROS - mediated HIF1␣ accumulation was reported to enhance the metastatic poten - tial of cells harboring the m . 13997G>A / MT - ND6 missense mutation ( Ishikawa et al . , 2008 ) . However , only one of these reports con - sidered the mutation load and the impact on CI function and / or assembly ( Sharma et al . , 2011 ) . In this regard , we have previously demonstrated that disassembling CI mutations are associated with HIF1␣ destabilization by immunohistochemical staining of onco - cytomas ( Porcelli et al . , 2010 ) . It is important to note that HIF1␣ turnover depends on the levels of two TCA metabolites , namely ␣ - ketoglutarate ( ␣ - KG ) and "
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