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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    ABSTRACT: Mitochondria play a key role in overall cell physiology and health by integrating cellular metabolism with cellular defense and repair mechanisms in response to physiological or environmental changes or stresses. In fact, dysregulation of mitochondrial stress responses and its consequences in the form of oxidative stress, has been linked to a wide variety of diseases including inborn errors of metabolism. In this review we will summarize how the functional state of mitochondria - and especially the concentration of reactive oxygen species (ROS), produced in connection with the respiratory chain - regulates cellular stress responses by redox regulation of nuclear gene networks involved in repair systems to maintain cellular homeostasis and health. Based on our own and other's studies we re-introduce the ROS triangle model and discuss how inborn errors of mitochondrial metabolism, by production of pathological amounts of ROS, may cause disturbed redox signalling and induce chronic cell stress with non-resolving or compromised cell repair responses and increased susceptibility to cell stress induced cell death. We suggest that this model may have important implications for those inborn errors of metabolism, where mitochondrial dysfunction plays a major role, as it allows the explanation of oxidative stress, metabolic reprogramming and altered signalling growth pathways that have been reported in many of the diseases. It is our hope that the model may facilitate novel ideas and directions that can be tested experimentally and used in the design of future new approaches for pre-symptomatic diagnosis and prognosis and perhaps more effective treatments of inborn errors of metabolism.
    Journal of Inherited Metabolic Disease 05/2015; 38(4). DOI:10.1007/s10545-015-9861-5 · 3.37 Impact Factor
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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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    ABSTRACT: Jaboticaba species (Plinia sp.) have attracted attention because of their significant levels of phenolic compounds, primarily anthocyanins and flavonols. Jaboticaba, termed the Brazilian berry, has emerged as a new functional food with potential health benefits. Plinia trunciflora (O. Berg) Kausel is one of the main species of jaboticaba that is naturally occurring and cultivated in Brazil. Thus, this study aimed to determine the macronutrient and phenolic compositions of P. trunciflora pulp and peel. Additionally, jaboticaba peel extract (JPE) was evaluated for its in vitro antioxidant activity and its capacity to modulate oxidative stress as well as mitochondrial function in human lung fibroblast cells (MRC-5). The macronutrient found to have the highest level in both the peel and pulp was carbohydrates, followed by the high fiber content of the peel. The total phenolic compounds and antho-cyanin levels were higher in the peel than in the pulp. High resolution mass spectrometry (HRMS) showed the presence of cyanidin-3-O-glucoside and kaempferol. Moreover, JPE was able to reduce the decreases in complex I activity and the ATP levels induced by H 2 O 2 and thereby decreased the oxidative stress in MRC-5 cells. These findings show a new role for jaboticaba as a mitochondrial protectant in pathological conditions where mitochondrial dysfunction is involved.
    Food Research International 02/2015; 70:15-22. DOI:10.1016/j.foodres.2015.01.032 · 2.82 Impact Factor
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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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    ABSTRACT: The aim of the present study is to clarify some aspects of the mechanisms of regulation of mitochondrial metabolism in neuroblastoma (NB) cells. Experiments were performed on murine Neuro-2a (N2a) cell line, and the same cells differentiated by all-trans-retinoic acid (dN2a) served as in vitro model of normal neurons. Oxygraphy and Metabolic Control Analysis (MCA) were applied to characterize the function of mitochondrial oxidative phosphorylation (OXPHOS) in NB cells. Flux control coefficients (FCCs) for components of the OXPHOS system were determined using titration studies with specific non-competitive inhibitors in the presence of exogenously added ADP. Respiration rates of undifferentiated Neuro-2a cells (uN2a) and the FCC of Complex-II in these cells were found to be considerably lower than those in dN2a cells. Our results show that NB is not an exclusively glycolytic tumor and could produce a considerable part of ATP via OXPHOS. Two important enzymes - hexokinase-2 and adenylate kinase-2 can play a role in the generation of ATP in NB cells. MCA has shown that in uN2a cells the key sites in the regulation of OXPHOS are complexes I, II and IV, whereas in dN2a cells complexes II and IV. Results obtained for the phosphate and adenine nucleotide carriers showed that in dN2a cells these carriers exerted lower control over the OXPHOS than in undifferentiated cells. The sum of FCCs for both types of NB cells was found to exceed significantly that for normal cells suggesting that in these cells the respiratory chain was somehow reorganized or assembled into large supercomplexes.
    Journal of Bioenergetics 09/2013; 46(1). DOI:10.1007/s10863-013-9529-5 · 3.21 Impact Factor
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