Hypoxia Decreases Cellular ATP Demand and Inhibits Mitochondrial Respiration of A549 Cells

Heerlein, K.; Schulze, Andreas; Hotz, Lorenz; Bärtsch, Peter; Mairbäurl, Heimo

doi:10.1165/rcmb.2004-0202oc

Cited by 72 publications

(60 citation statements)

References 41 publications

(42 reference statements)

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“…Inhibition of mitochondrial function by prolonged anoxia and subsequent recovery in the presence of Cd was concurrent with elevated levels of oxidative DNA lesions in Cd-exposed oysters. These changes are reminiscent of the typical mitochondrial alterations induced by intermittent oxygen deficiency in hypoxia-sensitive organisms, such as mammals (1,29,37,52,77), and suggest that Cd exposure may lead to the loss of the stress-resistant mitochondrial phenotype in oysters. Earlier studies showed that Cd can inhibit mitochondrial ETC and matrix enzymes and induce elevated rates of ROS generation in oysters (12,33).…”

Section: Discussionmentioning

confidence: 89%

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Kurochkin

Ivanina

Eilers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Kurochkin IO, Ivanina AV, Eilers S, Downs CA, May LA, Sokolova IM. Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica). Am J Physiol Regul Integr Comp Physiol 297: R1262-R1272, 2009. First published September 2, 2009 doi:10.1152/ajpregu.00324.2009.-Benthic marine organisms such as mollusks are often exposed to periodic oxygen deficiency (due to the tidal exposure and/or seasonal expansion of the oxygen-deficient dead zones) and pollution by metals [e.g., cadmium, (Cd)]. These stressors can strongly affect mollusks' survival; however, physiological mechanisms of their combined effects are not fully understood. We studied the effects of Cd exposure on metabolic responses to prolonged anoxia and subsequent recovery in anoxia-tolerant intertidal mollusks Crassostrea virginica (eastern oysters). Anoxia led to an onset of anaerobiosis indicated by accumulation of L-alanine, acetate, and succinate. Prolonged anoxia (for 6 days) caused a decline in the maximum activity of electron transport chain and ADP-stimulated (state 3) oxygen uptake by mitochondria (MO 2), but no change in the resting (state 4) MO 2 of oyster mitochondria, along with a slight but significant reduction of mitochondrial respiratory control ratio. During reoxygenation, there was a significant overshoot of mitochondrial MO 2 (by up to 70% above the normoxic steady-state values) in control oysters. Mild mitochondrial uncoupling during prolonged shutdown in anoxic tissues and a subsequent strong stimulation of mitochondrial flux during recovery may help to rapidly restore redox status and protect against elevated reactive oxygen species formation in oysters. Exposure to Cd inhibits anaerobic metabolism, abolishes reoxygenation-induced stimulation of mitochondrial MO 2, and leads to oxidative stress (indicated by accumulation of DNA lesions) and a loss of mitochondrial capacity during postanoxic recovery. This may result in increased sensitivity to intermittent hypoxia and anoxia in Cd-exposed mollusks and will have implications for their survival in polluted estuaries and coastal zones. air exposure; recovery; mitochondrial function; oxidative damage; mollusks PERIODICAL OXYGEN DEFICIENCY is an important environmental stressor in intertidal and coastal habitats. Short-term intermittent hypoxia/anoxia (from several hours to several days, depending on the state of the tides) often occurs in intertidal invertebrates during the low tide, and may also occur in tidal pools and shallow lagoons with limited water exchange (8,36,49). Furthermore, long-term severe hypoxia and anoxia triggered by anthropogenic release of nutrients has become a serious issue in many estuaries and coastal zones rivaling the climate change (18,22). In the coastal dead zones, benthic invertebrates including mollusks can be exposed to severe hypoxia or anoxia for prolonged periods (from weeks to up to several months) (10,22,34,46). Long-term oxygen deficiency often leads to the massive die-offs in species with limited or...

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Section: Discussionmentioning

confidence: 89%

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Kurochkin

Ivanina

Eilers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Our fi nding of intracellular ATP levels ( ‫ف‬ 3 mM) that are close to the K m of choline kinase for ATP ( ‫ف‬ 1.5 mM) ( 24 ) suggests that decreases in ATP levels in hypoxic cancer cells could also contribute to reduction in choline phosphorylation, an effect that could compound with changes in choline kinase expression and activity. In cells under moderate hypoxic stress, there are mechanisms that maintain ATP levels in a range that keeps the cell viable (25)(26)(27). This is usually done by coordinating various energy-supplying and energy-consuming processes.…”

Section: Discussionmentioning

confidence: 99%

Choline phosphorylation and regulation of transcription of choline kinase α in hypoxia

Bansal

Harris

DeGrado

2012

Journal of Lipid Research

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by choline kinase to form phosphocholine is the fi rst step of multistep Kennedy pathway ( 1 ) that synthesizes the major membrane phospholipid, phosphatidylcholine. Increased choline phosphorylation (primarily by choline kinase ␣ , ChK ␣ ) in tumor as compared with normal tissue has been reported in lung, breast, colorectal, and prostate cancers ( 2-5 ). This has motivated evaluation of cancer therapies involving choline kinase inhibition ( 6 ) and use of cancer imaging techniques with choline phosphorylation as a diagnostic metabolic step ( 7,8 ).Metabolism of choline in cancer cells is known to be sensitive to its microenvironment. Tracer studies in the mouse atrial cardiomyocyte tumor lineage, AT-1 ( 9 ), and 9L glioma allografts ( 10 ) showed that radiolabeled choline phosphorylation and accumulation is signifi cantly diminished in hypoxia. Our previous tracer studies with two human prostate cancer cell lines, PC-3 and LNCaP, showed 15% and 28% decreases in choline accumulation, respectively, after 4 h of anoxia (0% O 2 ) ( 11 ). After 24 h of anoxia, choline accumulation continued to decrease in both cell lines without loss of cellular viability. Because low oxygen exposure is a common factor in the microenvironment of tumors, it is important to understand the mechanisms of this effect and the implications for therapeutic and diagnostic applications involving choline metabolism.The goals of the present study were to utilize PC-3 prostate cancer cells to assess the effects of hypoxia on 1 ) steady-state levels of choline metabolites, 2 ) equilibrium status of choline phosphorylation, 3 ) radiolabeled choline uptake and phosphorylation, 4 ) ChK ␣ mRNA and protein levels, and 5 ) choline kinase activity. In this work, we demonstrate that choline phosphorylation is not at equilibrium In recent years, choline phospholipid metabolism has been widely studied in cancer research. Choline is an important precursor of phospholipids. Its phosphorylation

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“…A major factor in cell survival under low oxygen conditions is the ability of cells to increase glycolysis in order to maintain sufficient ATP levels [7,39]. Anoxia induced mild cell injury in both epithelial and microvascular endothelial cells, while 1 and 7 % oxygen was tolerated by both cell types.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Hypoxic Stress in Alveolar Epithelial Cells and Microvascular Endothelial Cells

Signorelli

Jennings

Leonard

et al. 2010

Cell Physiol Biochem

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Under hypoxic conditions eukaryotic cells and tissues undergo adaptive responses involving glycolysis, angiogenesis, vasoconstriction and inflammation. The underlying molecular mechanisms are not yet fully elucidated and are most likely cell and tissue specific. In the lung, alveolar epithelial cells and microvascular endothelial cells are highly sensitive to hypoxia and together orchestrate a rapid and sustained adaptive response. We examined the effect of different oxygen tensions on cell viability, glucose metabolism, key transcription factors and signaling molecules, in alveolar epithelial cells (A549) and microvascular endothelial cells (HMEC-1). Both cell types tolerated hypoxia without detectable cell injury. Hypoxia induced glycolysis in both epithelial and microvascular endothelial cells, although A549 cells exhibited a higher rate of glucose consumption. The transcription factor CREB (cAMP response element binding protein) was activated with decreasing oxygen tensions in both cell types. This effect was again more marked in A549 cells, demonstrating epithelial cells to be more oxygen sensitive. Activating Transcription Factor 3 (ATF-3) was heavily induced by hypoxia in A549 cells but not in HMEC-1 cells. Both cell types exhibited hypoxia induced secretion of VEGF and IL-6. Secretion of the vasoconstrictor endothelin-1 (ET1) was increased by hypoxia in HMEC-1 cells but decreased in A549 cells. These data reveal that both cell types exhibit an adaptive response to hypoxia but alveolar epithelial cells are generally more sensitive. ET-1 was oppositely regulated by decreased oxygen tensions in the investigated cell types. The present study further elucidates the adaptive molecular mechanisms in pulmonary hypoxia and demonstrates cell specific responses.

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Hypoxia Decreases Cellular ATP Demand and Inhibits Mitochondrial Respiration of A549 Cells

Cited by 72 publications

References 41 publications

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Cadmium affects metabolic responses to prolonged anoxia and reoxygenation in eastern oysters (Crassostrea virginica)

Choline phosphorylation and regulation of transcription of choline kinase α in hypoxia

Differential Effects of Hypoxic Stress in Alveolar Epithelial Cells and Microvascular Endothelial Cells

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