Zn2+ Inhibits α-Ketoglutarate-stimulated Mitochondrial Respiration and the Isolated α-Ketoglutarate Dehydrogenase Complex

Brown, Abraham M.; Kristal, Bruce S.; Effron, Michelle S.; Shestopalov, Alexander I.; Ullucci, Paul A.; Sheu, Kwan‐Fu Rex; Blass, John P.; Cooper, Arthur J. L.

doi:10.1074/jbc.275.18.13441

Cited by 145 publications

(123 citation statements)

References 56 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…Zinc ions have been shown to be proapoptotic under certain circumstances 51 and the solubilized ZnO released from the endosomes could be causing toxicity by inhibiting energy metabolism. [51][52][53] However, as Figure 10 shows, none of the three particles had any influence on the rate of proliferation of the cells.…”

Section: Zinc Oxidementioning

confidence: 97%

Minimal Intestinal Epithelial Cell Toxicity in Response to Short- and Long-Term Food-Relevant Inorganic Nanoparticle Exposure

McCracken

Zane

Knight

et al. 2013

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Toxicity of commercial nanoparticles of titania, silica, and zinc oxides is being investigated in this in vitro study. Particles of these compositions are found in many food items, and thus this study is directed toward particle behavior in simulated digestion media and their interaction with intestinal epithelial cell line C2BBe1, a clone of Caco-2 cells, originally isolated from a human colon cancer. Even though the primary particle size of all three particles was below 50 nm, the particles appeared as aggregates in culture media with a negatively charged surface. In the presence of pepsin (pH 2), the charge on the titania became positive, and silica was almost neutral and aggregated extensively, whereas ZnO dissolved. For silica and titania, treatment with simulated intestinal digestive solution led to a strongly negatively charged surface and particle sizes approaching values similar to those in media. On the basis of infrared spectroscopy, we concluded that the surface of silica and titania was covered with bile salts/proteins after this treatment. Transmission electron microscopy indicated that the C2BBe1 cells internalized all three particles. Toxicity assays included investigation of necrosis, apoptosis, membrane damage, and mitochondrial activity. Titania and SiO2 particles suspended in media at loading levels of 10 μg/cm2 exhibited no toxicity. With ZnO at the same loading level, mild toxicity was observed based only on the LDH assay and decrease of mitochondrial activity and not necrosis or apoptosis. Titania particles exposed to the simulated digestion media exhibited mild toxicity based on decrease of mitochondrial activity, likely due to transport of toxic bile salts via adsorption on the particle surface.

show abstract

Section: Zinc Oxidementioning

confidence: 97%

Minimal Intestinal Epithelial Cell Toxicity in Response to Short- and Long-Term Food-Relevant Inorganic Nanoparticle Exposure

McCracken

Zane

Knight

et al. 2013

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…In the lipoamide dehydrogenase reaction, superoxide was also produced and the ratio of superoxide and hydrogen peroxide generated in the reaction was found to be 1 : 9 (Bando & Aki 1991). Interestingly, it has been reported that Zn 2C , which could inhibit a-KGDH (Brown et al 2000), is able to stimulate the oxidase activity of the isolated lipoamide dehydrogenase (Gazaryan et al 2002). In light of the report that Zn 2C is also able to induce ROS generation in the mitochondria (Sensi et al 1999), it is possible that Zn 2C -induced ROS generation by lipoamide dehydrogenase could be of pathological importance.…”

Section: A-kgdh As a Generator Of Oxidative Stressmentioning

confidence: 98%

Section: A-kgdh Is a Crucial Target Of Reactive Oxygen Species In Thementioning

confidence: 99%

“…It has been reported that Zn 2C , in submicromolar concentrations, induces reversible inhibition of the purified a-KGDH and inhibits respiration in liver mitochondria, the a-ketoglutaratedependent respiration showing the highest Zn 2C -sensitivity (Brown et al 2000). Zn 2C also inhibited glutamate dehydrogenase and PDH, but not succinate dehydrogenase or malate dehydrogenase (Brown et al 2000). Zn 2C has been implicated in the pathogenesis of excitotoxic injury (Weiss et al 2000;Dineley et al 2003;Frederickson et al 2004), another condition in which oxidative stress is a key event (Coyle & Puttfarcken 1993;Lafon-Cazal et al 1993;Reynolds & Hastings 1995;Patel et al 1996;Wang & Thayer 1996;White & Reynolds 1996).…”

Section: A-kgdh Is a Crucial Target Of Reactive Oxygen Species In Thementioning

confidence: 99%

See 1 more Smart Citation

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

Tretter

Ádám-Vizi

2005

Phil. Trans. R. Soc. B

370

285

View full text Add to dashboard Cite

Alpha-ketoglutarate dehydrogenase (a-KGDH) is a highly regulated enzyme, which could determine the metabolic flux through the Krebs cycle. It catalyses the conversion of a-ketoglutarate to succinylCoA and produces NADH directly providing electrons for the respiratory chain. a-KGDH is sensitive to reactive oxygen species (ROS) and inhibition of this enzyme could be critical in the metabolic deficiency induced by oxidative stress. Aconitase in the Krebs cycle is more vulnerable than a-KGDH to ROS but as long as a-KGDH is functional NADH generation in the Krebs cycle is maintained. NADH supply to the respiratory chain is limited only when a-KGDH is also inhibited by ROS. In addition being a key target, a-KGDH is able to generate ROS during its catalytic function, which is regulated by the NADH/NAD C ratio. The pathological relevance of these two features of a-KGDH is discussed in this review, particularly in relation to neurodegeneration, as an impaired function of this enzyme has been found to be characteristic for several neurodegenerative diseases.

show abstract

“…Reports indicate that accumulation of intracellular zinc, as a consequence of either exogenous administration or release from intracellular stores by reactive oxygen species or nitrosation, activates pro-apoptotic molecules like p38 and potassium channels, leading to cell death (Kim et al 1999;McLaughlin et al 2001;TruongTran et al 2001). Increased intracellular zinc levels may also induce cell death by inhibition of the energy metabolism (Brown et al 2000;Sheline et al 2000). In the context of its apoptosis-inducing properties, zinc has been shown to increase the expression of Bax, leading to a decrease in the Bcl-2/Bax ratio (Feng et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Transient receptor potential melastatin type 7 channels are involved in zinc-induced apoptosis in gastric cancer

Kim¹

2011

Animal Cells and Systems

View full text Add to dashboard Cite

Zn2+ Inhibits α-Ketoglutarate-stimulated Mitochondrial Respiration and the Isolated α-Ketoglutarate Dehydrogenase Complex

Cited by 145 publications

References 56 publications

Minimal Intestinal Epithelial Cell Toxicity in Response to Short- and Long-Term Food-Relevant Inorganic Nanoparticle Exposure

Minimal Intestinal Epithelial Cell Toxicity in Response to Short- and Long-Term Food-Relevant Inorganic Nanoparticle Exposure

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

Transient receptor potential melastatin type 7 channels are involved in zinc-induced apoptosis in gastric cancer

Contact Info

Product

Resources

About