Zinc toxicity alters mitochondrial metabolism and leads to decreased ATP production in hepatocytes

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada.
Journal of Applied Toxicology (Impact Factor: 2.98). 03/2008; 28(2):175-82. DOI: 10.1002/jat.1263
Source: PubMed


Although zinc (Zn) is a known environmental toxicant, its impact on the cellular energy-producing machinery is not well established. This study investigated the influence of this divalent metal on the oxidative ATP producing network in human hepatocellular carcinoma (HepG2) cells. Zn-challenged cells contained more oxidized proteins and lipids compared with control cells. Zn severely impeded mitochondrial functions by inhibiting aconitase, alpha-ketoglutarate dehydrogenase, isocitrate dehydrogenase-NAD+ dependent, succinate dehydrogenase and cytochrome C oxidase Zn-exposed cells had a disparate mitochondrial metabolism compared with the control cells and produced significantly less ATP. However, the expression of isocitrate dehydrogenase-NADP+ dependent was more prominent in cells treated with Zn. Hence, Zn-induced pathologies may be due to the inability of the mitochondria to generate energy effectively.

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    • "The generation of this oxidant and nitrating agent can have potentially toxic ramifications via the nitration of tyrosine residues and s-nitrosylation of cysteine moieties on vital proteins in the mitochondrion (Pacher et al., 2007). Moreover, exposure to bioavailable cationic metals such as Al and Zn can lead to an increase in ROS and displace Fe from the active site of some proteins, such as aconitase (ACN) (Lemire et al., 2008; Han et al., 2013). Free Fe poses a threat to cells due to its participation in Fenton chemistry, which further increases the concentration of detrimental • HO (Ahlqvist et al., 2015). "
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    ABSTRACT: The liver is involved in a variety of critical biological functions including the homeostasis of glucose, fatty acids, amino acids, and the synthesis of proteins that are secreted in the blood. It is also at the forefront in the detoxification of noxious metabolites that would otherwise upset the functioning of the body. As such, this vital component of the mammalian system is exposed to a notable quantity of toxicants on a regular basis. It therefore comes as no surprise that there are over a hundred disparate hepatic disorders, encompassing such afflictions as fatty liver disease, hepatitis, and liver cancer. Most if not all of liver functions are dependent on energy, an ingredient that is primarily generated by the mitochondrion, the power house of all cells. This organelle is indispensable in providing adenosine triphosphate (ATP), a key effector of most biological processes. Dysfunctional mitochondria lead to a shortage in ATP, the leakage of deleterious reactive oxygen species (ROS), and the excessive storage of fats. Here we examine how incapacitated mitochondrial bioenergetics triggers the pathogenesis of various hepatic diseases. Exposure of liver cells to detrimental environmental hazards such as oxidative stress, metal toxicity, and various xenobiotics results in the inactivation of crucial mitochondrial enzymes and decreased ATP levels. The contribution of the latter to hepatic disorders and potential therapeutic cues to remedy these conditions are elaborated.
    Frontiers in Cell and Developmental Biology 06/2015; 3:40. DOI:10.3389/fcell.2015.00040
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    • "It has been well documented that Cd 2+ can result in extensive toxic effect on cell physiology by disrupting enzymatic functions through its binding to the functional groups or replacing other metal ions therein [2]. Although Zn 2+ is a micronutrient for cell growth and metabolism that regulates gene expression through the role of zinc fingers or acting as a cofactor for many metalloenzymes , it is also toxic at high concentrations [3] [4]. Microalgae can remove heavy metal ions, either by adsorption as biosorbents or by adsorption together with metabolic uptake during their cultures [5] [6]. "
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    ABSTRACT: Microalgae are attracting attention due to their potentials in mitigating CO2 emissions and removing environmental pollutants. However, harvesting microalgal biomass from diluted cultures is one of the bottlenecks for developing economically viable processes for this purpose. Microalgal cells can be harvested by cost-effective sedimentation when flocculating strains are used. In this study, the removal of Zn2+ and Cd2+ by the flocculating Chlorella vulgaris JSC-7 was studied. The experimental results indicated that more than 80% Zn2+ and 60% Cd2+ were removed by the microalgal culture within 3 days in the presence up to 20.0 mg/L Zn2+ and 4.0 mg/L Cd2+, respectively, which were much higher than that observed with the culture of the non-flocculating C. vulgaris CNW11. Furthermore, the mechanism underlying this phenomenon was explored by investigating the effect of Zn2+ and Cd2+ on the growth and metabolic activities of the microalgal strains. It was found that the flocculation of the microalga improved its growth, synthesis of photosynthetic pigments and antioxidation activity under the stressful conditions, indicating a better tolerance to the heavy metal ions for a potential in removing them more efficiently from contaminated wastewaters, together with a bioremediation of other nutritional components contributed to the eutrophication of aquatic ecosystems.
    Journal of Hazardous Materials 05/2015; 289:38-45. · 4.53 Impact Factor
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    • "A decrease in ATP results in activation of PFK as there is a demand for energy and, as glycolysis is the first step in energy metabolism by the cell, PFK is activated to produce ATP as well as to produce pyruvate for oxidation in the TCA cycle. Zinc is known to inhibit ICDH in cultured hepatocytes and may interfere with a number of key enzymes in the TCA cycle, resulting in changes in ATP production (Lemire et al., 2008). We identified a number of disaccharides in the GC–MS analyses that had distinct GC-retention times and mass spectra from commonly reported disaccharides (i.e., trehalose, maltose or sucrose) and were decreased following Zn exposure. "
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    ABSTRACT: Measuring biological responses in resident biota is a commonly used approach to monitoring polluted habitats. The challenge is to choose sensitive and, ideally, stressor-specific endpoints that reflect the responses of the ecosystem. Metabolomics is a potentially useful approach for identifying sensitive and consistent responses since it provides a holistic view to understanding the effects of exposure to chemicals upon the physiological functioning of organisms. In this study, we exposed the aquatic non-biting midge, Chironomus tepperi, to two concentrations of zinc chloride and measured global changes in polar metabolite levels using an untargeted gas chromatography-mass spectrometry (GC-MS) analysis and a targeted liquid chromatography-mass spectrometry (LC-MS) analysis of amine-containing metabolites. These data were correlated with changes in the expression of a number of target genes. Zinc exposure resulted in a reduction in levels of intermediates in carbohydrate metabolism (i.e., glucose 6-phosphate, fructose 6-phosphate and disaccharides) and an increase in a number of TCA cycle intermediates. Zinc exposure also resulted in decreases in concentrations of the amine containing metabolites, lanthionine, methionine and cystathionine, and an increase in metallothionein gene expression. Methionine and cystathionine are intermediates in the transsulfuration pathway which is involved in the conversion of methionine to cysteine. These responses provide an understanding of the pathways affected by zinc toxicity, and how these effects are different to other heavy metals such as cadmium and copper. The use of complementary metabolomics analytical approaches was particularly useful for understanding the effects of zinc exposure and importantly, identified a suite of candidate biomarkers of zinc exposure useful for the development of biomonitoring programs. Copyright © 2015 Elsevier B.V. All rights reserved.
    Aquatic toxicology (Amsterdam, Netherlands) 03/2015; 162. DOI:10.1016/j.aquatox.2015.03.009 · 3.45 Impact Factor
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