Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis

Ayala‐Peña, Sylvette

doi:10.1016/j.freeradbiomed.2013.04.017

Cited by 115 publications

(69 citation statements)

References 143 publications

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“…A major by-product of ROS attack of genomic DNA is the pre-mutagenic lesion 8-OHdG, which results in G-to-T transversions [35]. The main defense against the mutagenic effect of 8-OHdG is the base excision repair pathway, which, in eukaryotes, is initiated by the OGG1 protein, a DNA glycosylase that catalyzes the excision of 8-OHdG from DNA [36]. Improper or incomplete repairs of DNA damage due to oxidative stress may result in DNA strand breaks, cell cycle arrest, apoptosis, and mitochondrial dysfunction, which in turn increases ROS production.…”

Section: Discussionmentioning

confidence: 99%

Cadmium Exposure Enhances Bisphenol A-Induced Genotoxicity through 8-Oxoguanine-DNA Glycosylase-1 OGG1 Inhibition in NIH3T3 Fibroblast Cells

Chen

Liu²,

Lu³

et al. 2016

Cell Physiol Biochem

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Background: Both cadmium (Cd) and bisphenol A (BPA) are commonly encountered in humans' daily activities, but their combined genotoxic effects remain unclear. Methods: In the present study, we exposed a mouse embryonic fibroblast cell line (NIH3T3) to Cd for 24 h, followed by a 24 h BPA exposure to evaluate toxicity. The cytotoxicity was evaluated by viability with CCK-8 assay and lactate dehydrogenase (LDH) release. Reactive oxygen species (ROS) production was measured by 2′,7′-dichlorofluorescein diacetate (DCFH-DA). And DNA damage was measured by 8-hydroxydeoxyguanosine (8-OHdG), phosphorylated H2AX (γH2AX) and the comet assay. The flow cytometry was used to detect cell cycle distribution, and apoptosis was determined by TUNEL assay and western blot against poly-ADP-ribose polymerase (PARP). Results: The results showed that Cd or BPA treatments alone (with the exception of BPA exposure at 50 μM) did not alter cell viability. However, pre-treatment with Cd aggravated the BPA-induced reduction in cell viability; increased BPA-induced LDH release, ROS production, DNA damage and G2 phase arrest; and elevated BPA-induced TUNEL-positive cells and the expression levels of cleaved PARP. Cd exposure concurrently decreased the expression of 8-oxoguanine-DNA glycosylase-1 (OGG1), whereas OGG1 over-expression abolished the enhancement of Cd on BPA-induced genotoxicity and cytotoxicity. Conclusion: These findings indicate that Cd exposure aggravates BPA-induced genotoxicity and cytotoxicity through OGG1 inhibition.

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Section: Discussionmentioning

confidence: 99%

Cadmium Exposure Enhances Bisphenol A-Induced Genotoxicity through 8-Oxoguanine-DNA Glycosylase-1 OGG1 Inhibition in NIH3T3 Fibroblast Cells

Chen

Liu²,

Lu³

et al. 2016

Cell Physiol Biochem

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“…12 During replication, cytosine or adenine bases incorporate into 8-OHdG resulting in guanine-cytosine thymine-adenine mismatch, and 8-oxoguanine glycosylase (OGG1) of the BER system repairs 8-OHdG lesions. 37,38 While DNA polymerase beta is responsible for incorporating the correct base in the nuclear DNA, POLG is important for the mtDNA. 13,39,40 In the pathogenesis of diabetic retinopathy, 8-OHdG levels are elevated and OGG1 accumulation in the mitochondria is attenuated, mtDNA damage is more extensive at the D-loop region than other regions of mtDNA, and the binding of POLG at the D-loop region is compromised and mtDNA transcription is impaired.…”

Section: Discussionmentioning

confidence: 99%

Retinal Mitochondrial DNA Mismatch Repair in the Development of Diabetic Retinopathy, and Its Continued Progression After Termination of Hyperglycemia

Mishra¹,

Kowluru²

2014

Investigative Ophthalmology & Visual Science

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Citation: Mishra M, Kowluru RA. Retinal mitochondrial DNA mismatch repair in the development of diabetic retinopathy, and its continued progression after termination of hyperglycemia. Invest Ophthalmol Vis Sci. 2014;55:6960-6967. DOI:10.1167/ iovs.14-15020 PURPOSE. Mitochondrial DNA (mtDNA) is damaged in the retina in diabetes, and mitochondria copy numbers are decreased. The displacement-loop (D-loop) of the mtDNA, the region with transcription/replication elements, experiences more damage than other regions of mtDNA. Our aim was to examine the role of DNA mismatch repair (MMR) in mitochondria homeostasis in diabetic retinopathy, and in its continued progression after cessation of hyperglycemia.METHODS. Effect of hyperglycemia on sequence variants in the D-loop region was investigated in retinal endothelial cells and in the retina from streptozotocin-induced diabetic rats using mismatch-specific surveyor nuclease. The role of MMR machinery in mtDNA damage and mitochondrial respiration was investigated in retinal endothelial cells overexpressing Mlh1, an MMR enzyme mainly associated with mtDNA polymerase gamma, or Msh2 (associated with nuclear polymerase beta). CONCLUSIONS. Due to a compromised MMR system, the sequence variants in the D-loop region were not repaired, and that resulted in impaired mtDNA transcription. Mitochondria become dysfunctional, and they continued to be dysfunctional even after hyperglycemia was terminated, contributing to the development, and progression of diabetic retinopathy. Thus, strategies targeting mitochondrial MMR machinery could help maintain mitochondria homeostasis, and inhibit the development of diabetic retinopathy and its continued progression. RESULTS. Hyperglycemia increased sequence variants in

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“…As a structural analogue of succinate, 3-NPA covalently and irreversibly binds to the active site of the enzyme thereby preventing complex-II-mediated FADH 2 generation [17]. In neurological research, in which 3-NPA is widely used to damage dopaminergic neurons in animal models of HD or Parkinson's disease [18,19], it has been suggested that the mechanism underlying 3-NPA toxicity involves increased production of reactive oxygen species (ROS) [20].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial succinate dehydrogenase is involved in stimulus-secretion coupling and endogenous ROS formation in murine beta cells

et al. 2015

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Aims/hypothesis Generation of reduction equivalents is a prerequisite for nutrient-stimulated insulin secretion. Mitochondrial succinate dehydrogenase (SDH) fulfils a dual function with respect to mitochondrial energy supply: (1) the enzyme is part of mitochondrial respiratory chains; and (2) it catalyses oxidation of succinate to fumarate in the Krebs cycle. The aim of our study was to elucidate the significance of SDH for beta cell stimulus-secretion coupling (SSC). Methods Mitochondrial variables, reactive oxygen species (ROS) and cytosolic Ca 2+ concentration ([Ca 2+ ] c ) were measured by fluorescence techniques and insulin release by radioimmunoassay in islets or islet cells of C57Bl/6N mice. Results Inhibition of SDH with 3-nitropropionic acid (3-NPA) or monoethyl fumarate (MEF) reduced glucosestimulated insulin secretion. Inhibition of the ATP-sensitive K + channel (K ATP channel) partly prevented this effect, whereas potentiation of antioxidant defence by superoxide dismutase mimetics (TEMPOL and mito-TEMPO) or by nuclear factor erythroid 2-related factor 2 (Nrf-2)-mediated upregulat i o n o f a n t i o x i d a n t e n z y m e s ( o l t i p r a z , t e r tbutylhydroxyquinone) did not diminish the inhibitory influence of 3-NPA. Blocking SDH decreased glucose-stimulated increase in intracellular FADH 2 concentration without alterations in NAD(P)H. In addition, 3-NPA and MEF drastically reduced glucose-induced hyperpolarisation of mitochondrial membrane potential, indicative of decreased ATP production. As a consequence, the glucose-stimulated rise in [Ca 2+ ] c was significantly delayed and reduced. Acute application of 3-NPA interrupted glucose-driven oscillations of [Ca 2+ ] c . 3-NPA per se did not elevate intracellular ROS, but instead prevented glucose-induced ROS accumulation. Conclusions/interpretation SDH is an important regulator of insulin secretion and ROS production. Inhibition of SDH interrupts membrane-potential-dependent SSC, pointing to a pivotal role of mitochondrial FAD/FADH 2 homeostasis for the maintenance of glycaemic control.

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Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis

Cited by 115 publications

References 143 publications

Cadmium Exposure Enhances Bisphenol A-Induced Genotoxicity through 8-Oxoguanine-DNA Glycosylase-1 OGG1 Inhibition in NIH3T3 Fibroblast Cells

Cadmium Exposure Enhances Bisphenol A-Induced Genotoxicity through 8-Oxoguanine-DNA Glycosylase-1 OGG1 Inhibition in NIH3T3 Fibroblast Cells

Retinal Mitochondrial DNA Mismatch Repair in the Development of Diabetic Retinopathy, and Its Continued Progression After Termination of Hyperglycemia

Mitochondrial succinate dehydrogenase is involved in stimulus-secretion coupling and endogenous ROS formation in murine beta cells

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