DHA Protects Against Zinc Mediated Alterations in Neuronal Cellular Bioenergetics

McGee, Sean L.; Sadli, Nadia; Morrison, Shona; Swinton, Courtney; Suphioglu, Cenk

doi:10.1159/000331724

Cited by 19 publications

(23 citation statements)

References 21 publications

(25 reference statements)

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“…Recently, we have reported that DHA could protect against zinc-altered mitochondrial dysfunction in M17 cells [10]. Part of this effect could be due to the neuroprotective function of DHA in limiting cellular zinc uptake through decreasing ZnT-3 zinc transporter expression levels [6,20], which in turn inhibits zinc toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…However, the mechanism of zinc toxicity is unknown, but evidence suggests that zinc induces cellular apoptosis through inhibition of adenosine triphosphate (ATP) synthesis [8,9], increase in the production of reactive oxygen species (ROS) and eventual loss of mitochondrial membrane potential ∆Ψ m [9]. Recently, we reported that DHA protects against zinc-mediated alterations in human neuronal cell bioenergetics and mitochondrial function [10]. …”

Section: Introductionmentioning

confidence: 99%

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Effect of DHA and CoenzymeQ10 Against A�- and Zinc-Induced Mitochondrial Dysfunction in Human Neuronal Cells

Sadli¹,

Barrow²,

McGee

et al. 2013

Cell Physiol Biochem

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Background: Beta-amyloid (Aβ) protein is a key factor in the pathogenesis of Alzheimer's disease (AD) and it has been reported that mitochondria is involved in the biochemical pathway by which Aβ can lead to neuronal dysfunction. Coenzyme Q10 (CoQ10) is an essential cofactor involved in the mitochondrial electron transport chain and has been suggested as a potential therapeutic agent in AD. Zinc toxicity also affects cellular energy production by decreasing oxygen consumption rate (OCR) and ATP turnover in human neuronal cells, which can be restored by the neuroprotective effect of docosahexaenoic acid (DHA). Method: In the present study, using Seahorse XF-24 Metabolic Flux Analysis we investigated the effect of DHA and CoQ10 alone and in combination against Aβ- and zinc-mediated changes in the mitochondrial function of M17 neuroblastoma cell line. Results: Here, we observed that DHA is specifically neuroprotective against zinc-triggered mitochondrial dysfunction, but does not directly affect Aβ neurotoxicity. CoQ10 has shown to be protective against both Aβ- and zinc-induced alterations in mitochondrial function. Conclusion: Our results indicate that DHA and CoQ10 may be useful for the prevention, treatment and management of neurodegenerative diseases such as AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of DHA and CoenzymeQ10 Against A�- and Zinc-Induced Mitochondrial Dysfunction in Human Neuronal Cells

Sadli¹,

Barrow²,

McGee

et al. 2013

Cell Physiol Biochem

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“…Following standardization using an established protocol, the basal oxygen consumption (‘respiratory’) rate in xL3s was measured using the Seahorse XF24 flux analyser (Seahorse Biosciences, USA) (McGee et al., 2011). In brief, 450 μl of LB* + 1% DMSO containing 100 μM of tolfenpyrad (‘hit’ compound) or 100 μM of moxidectin (control; not known to inhibit respiration), or LB* + 1% DMSO alone (untreated control) were transferred in quadruplicate to the wells of a 24-well plate (Seahorse XF24).…”

Section: Methodsmentioning

confidence: 99%

Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole worm

Preston

Jiao

Jabbar

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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There is a substantial need to develop new medicines against parasitic diseases via public-private partnerships. Based on high throughput phenotypic screens of largely protozoal pathogens and bacteria, the Medicines for Malaria Venture (MMV) has recently assembled an open-access ‘Pathogen Box’ containing 400 well-curated chemical compounds. In the present study, we tested these compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). In an optimised, whole-organism screening assay, using exsheathed third-stage (xL3) and fourth-stage (L4) larvae, we measured the inhibition of larval motility, growth and development of H. contortus. We also studied the effect of the ‘hit’ compound on mitochondrial function by measuring oxygen consumption. Among the 400 Pathogen Box compounds, we identified one chemical, called tolfenpyrad (compound identification code: MMV688934) that reproducibly inhibits xL3 motility as well as L4 motility, growth and development, with IC50 values ranging between 0.02 and 3 μM. An assessment of mitochondrial function showed that xL3s treated with tolfenpyrad consumed significantly less oxygen than untreated xL3s, which was consistent with specific inhibition of complex I of the respiratory electron transport chain in arthropods. Given that tolfenpyrad was developed as a pesticide and has already been tested for absorption, distribution, excretion, biotransformation, toxicity and metabolism, it shows considerable promise for hit-to-lead optimisation and/or repurposing for use against H. contortus and other parasitic nematodes. Future work should assess its activity against hookworms and other pathogens that cause neglected tropical diseases.

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“…Cells were washed and incubated at 37°C in DMEM containing either 5 mmol/L glucose, 1 mmol/L pyruvate, and 1 mmol/L glutamate or 25 mmol/L glucose, 1 mmol/L pyruvate, and 1 mmol/L glutamate, pH 7.4, for 2 h. Three basal OCR measurements were performed, and these were then repeated following sequential exposure to the ATP synthase inhibitor oligomycin (1 mmol/L), the proton ionophore FCCP (1 mmol/L), and the complex III inhibitor antimycin A (1 mmol/L). Calculations of the respiratory parameters of mitochondrial function were then completed (27). At the end of the assay, the number of cells was determined in each well using the CyQuant Cell Proliferation Assay kit (Molecular Probes) according to the instructions of the manufacturer.…”

Section: Lentiviral Infection Of Ptecs and Cellular Oxygen Consumptionmentioning

confidence: 99%

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

et al. 2016

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Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with dual roles in redox signaling and programmed cell death. Deficiency in AIF is known to result in defective oxidative phosphorylation (OXPHOS), via loss of complex I activity and assembly in other tissues. Because the kidney relies on OXPHOS for metabolic homeostasis, we hypothesized that a decrease in AIF would result in chronic kidney disease (CKD). Here, we report that partial knockdown of Aif in mice recapitulates many features of CKD, in association with a compensatory increase in the mitochondrial ATP pool via a shift toward mitochondrial fusion, excess mitochondrial reactive oxygen species production, and Nox4 upregulation. However, despite a 50% lower AIF protein content in the kidney cortex, there was no loss of complex I activity or assembly. When diabetes was superimposed onto Aif knockdown, there were extensive changes in mitochondrial function and networking, which augmented the renal lesion. Studies in patients with diabetic nephropathy showed a decrease in AIF within the renal tubular compartment and lower AIFM1 renal cortical gene expression, which correlated with declining glomerular filtration rate. Lentiviral overexpression of Aif1m rescued glucose-induced disruption of mitochondrial respiration in human primary proximal tubule cells. These studies demonstrate that AIF deficiency is a risk factor for the development of diabetic kidney disease.

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DHA Protects Against Zinc Mediated Alterations in Neuronal Cellular Bioenergetics

Cited by 19 publications

References 21 publications

Effect of DHA and CoenzymeQ10 Against A�- and Zinc-Induced Mitochondrial Dysfunction in Human Neuronal Cells

Effect of DHA and CoenzymeQ10 Against A�- and Zinc-Induced Mitochondrial Dysfunction in Human Neuronal Cells

Screening of the ‘Pathogen Box’ identifies an approved pesticide with major anthelmintic activity against the barber's pole worm

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

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