Warburg and Crabtree Effects in Premalignant Barrett's Esophagus Cell Lines with Active Mitochondria

Suchorolski, Martin T.; Paulson, Thomas G.; Sanchez, Carissa A.; Hockenbery, David M.; Reid, Brian J.

doi:10.1371/journal.pone.0056884

Cited by 35 publications

(22 citation statements)

References 38 publications

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“…This data suggests that MMA(III) toxicity leads to a compensatory increase in glycolysis when mitochondrial function is impaired, also known as the Warburg effect (Suchorolski et al 2013) (Figure 2D,E). Treatment with iAs(III) led to a robust increase in basal ECARs (Figure 2D) but maximal ECARs were not significantly affected (Figure 2E), suggesting that treatment of VSMCs with iAs(III) leads to a partial upregulation of ECAR.…”

Section: Resultsmentioning

confidence: 92%

“…Hence, a decrease in the ratio of the mean OCR to ECAR associated with MMA(III) exposure (Figure 7) is an indicator of a compensatory upregulation of glycolysis as a result of mitochondrial dysfunction. Given that MMA(III) is known to adversely affect the functioning of the electron transport chain (ETC) (Naranmandura et al 2011), an increase in glycolysis may be a compensatory mechanism to ensure cellular survival, somewhat akin to the Warburg effect (Suchorolski et al 2013) due to mitochondrial impairment. However, it is worth noting that this increase in ECARs caused by MMA(III) exposure does not lead to an increase in cytosolic ATP levels under conditions that favor mitochondrial ATP production (Figure 3), or in glycolytic conditions (data not shown), suggesting that either MMA(III) elicits a futile upregulation of glycolysis or that non-mitochondrial sources of ROS (e.g.…”

Section: Discussionmentioning

confidence: 99%

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Monomethylarsonous acid, but not inorganic arsenic, is a mitochondria-specific toxicant in vascular smooth muscle cells

Pace

Banerjee

Welch

et al. 2016

Toxicology in Vitro

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Arsenic exposure has been implicated as a risk factor for cardiovascular diseases, metabolic disorders, and cancer, yet the role mitochondrial dysfunction plays in the cellular mechanisms of pathology is largely unknown. To investigate arsenic-induced mitochondrial dysfunction in vascular smooth muscle cells (VSMCs), we exposed rat aortic smooth muscle cells (A7r5) to inorganic arsenic (iAs(III)) and its metabolite monomethylarsonous acid (MMA(III)) and compared their effects on mitochondrial function and oxidative stress. Our results indicate that MMA(III) is significantly more toxic to mitochondria than iAs(III). Exposure of VSMCs to MMA(III), but not iAs(III), significantly decreased basal and maximal oxygen consumption rates and concomitantly increased compensatory extracellular acidification rates, a proxy of glycolysis. Treatment with MMA(III) significantly increased hydrogen peroxide and superoxide levels compared to iAs(III). Exposure to MMA(III) resulted in significant decreases in mitochondrial ATP, aberrant perinuclear clustering of mitochondria, and decreased mitochondrial content. Mechanistically, we observed that mitochondrial superoxide and hydrogen peroxide contribute to mitochondrial toxicity, as treatment of cells with MnTBAP (a mitochondrial superoxide dismutase mimetic) and catalase significantly reduced mitochondrial respiration deficits and cell death induced by both arsenic compounds. Overall, our data demonstrates that MMA(III) is a mitochondria-specific toxicant that elevates mitochondrial and non-mitochondrial sources of ROS.

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Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Monomethylarsonous acid, but not inorganic arsenic, is a mitochondria-specific toxicant in vascular smooth muscle cells

Pace

Banerjee

Welch

et al. 2016

Toxicology in Vitro

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“…Respiration and Glycolysis-HeLa cells are routinely grown in high glucose medium and are adapted to rely on a high rate of glycolysis to survive, which consequently suppresses their maximal respiratory capacity (32) through the Crabtree/Warburg effect (33). Hence, we investigated the effects of reducing the levels of endogenous mOGT by siRNA on the bioenergetic status of HeLa cells, in conditions favorable for either glycolysis or mitochondrial oxidative phosphorylation (32).…”

Section: Effects Of Reduction Of Endogenous Mogt On Mitochondrialmentioning

confidence: 99%

Mitochondrial O-GlcNAc Transferase (mOGT) Regulates Mitochondrial Structure, Function, and Survival in HeLa Cells

Sacoman

Dagda

Burnham-Marusich

et al. 2017

Journal of Biological Chemistry

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Edited by Gerald W. HartO-Linked N-acetylglucosamine transferase (OGT) catalyzes O-GlcNAcylation of target proteins and regulates numerous biological processes. OGT is encoded by a single gene that yields nucleocytosolic and mitochondrial isoforms. To date, the role of the mitochondrial isoform of OGT (mOGT) remains largely unknown. Using high throughput proteomics, we identified 84 candidate mitochondrial glycoproteins, of which 44 are novel. Notably, two of the candidate glycoproteins identified (cytochrome oxidase 2 (COX2) and NADH:ubiquinone oxidoreductase core subunit 4 (MT-ND4)) are encoded by mitochondrial DNA. Using siRNA in HeLa cells, we found that reducing endogenous mOGT expression leads to alterations in mitochondrial structure and function, including Drp1-dependent mitochondrial fragmentation, reduction in mitochondrial membrane potential, and a significant loss of mitochondrial content in the absence of mitochondrial ROS. These defects are associated with a compensatory increase in oxidative phosphorylation per mitochondrion. mOGT is also critical for cell survival; siRNA-mediated knockdown of endogenous mOGT protected cells against toxicity mediated by rotenone, a complex I inhibitor. Conversely, reduced expression of both nucleocytoplasmic (ncOGT) and mitochondrial (mOGT) OGT isoforms is associated with increased mitochondrial respiration and elevated glycolysis, suggesting that ncOGT is a negative regulator of cellular bioenergetics. Last, we determined that mOGT is probably involved in the glycosylation of a restricted set of mitochondrial targets. We identified four proteins implicated in mitochondrial biogenesis and metabolism regulation as candidate substrates of mOGT, including leucine-rich PPR-containing protein and mitochondrial aconitate hydratase. Our findings suggest that mOGT is catalytically active in vivo and supports mitochondrial structure, health, and survival, whereas ncOGT predominantly regulates cellular bioenergetics.

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“…3b). These significant pathways included pathways for oxidative phosphorylation32, glutathione metabolism33, ribosome3435 and proteasome36.…”

Section: Resultsmentioning

confidence: 99%

Identifying reproducible cancer-associated highly expressed genes with important functional significances using multiple datasets

Huang

Guo

et al. 2016

Sci Rep

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Identifying differentially expressed (DE) genes between cancer and normal tissues is of basic importance for studying cancer mechanisms. However, current methods, such as the commonly used Significance Analysis of Microarrays (SAM), are biased to genes with low expression levels. Recently, we proposed an algorithm, named the pairwise difference (PD) algorithm, to identify highly expressed DE genes based on reproducibility evaluation of top-ranked expression differences between paired technical replicates of cells under two experimental conditions. In this study, we extended the application of the algorithm to the identification of DE genes between two types of tissue samples (biological replicates) based on several independent datasets or sub-datasets of a dataset, by constructing multiple paired average gene expression profiles for the two types of samples. Using multiple datasets for lung and esophageal cancers, we demonstrated that PD could identify many DE genes highly expressed in both cancer and normal tissues that tended to be missed by the commonly used SAM. These highly expressed DE genes, including many housekeeping genes, were significantly enriched in many conservative pathways, such as ribosome, proteasome, phagosome and TNF signaling pathways with important functional significances in oncogenesis.

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Warburg and Crabtree Effects in Premalignant Barrett's Esophagus Cell Lines with Active Mitochondria

Cited by 35 publications

References 38 publications

Monomethylarsonous acid, but not inorganic arsenic, is a mitochondria-specific toxicant in vascular smooth muscle cells

Monomethylarsonous acid, but not inorganic arsenic, is a mitochondria-specific toxicant in vascular smooth muscle cells

Mitochondrial O-GlcNAc Transferase (mOGT) Regulates Mitochondrial Structure, Function, and Survival in HeLa Cells

Identifying reproducible cancer-associated highly expressed genes with important functional significances using multiple datasets

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