Prenatal exposure to oxidative phosphorylation xenobiotics and late-onset Parkinson disease

Iglesias, Eldris; Pesini, Alba; Garrido-Pérez, Nuria; Meade, Patricia; Bayona‐Bafaluy, M. Pilar; Montoya, Julio; Ruiz‐Pesini, Eduardo

doi:10.1016/j.arr.2018.04.006

Cited by 13 publications

(9 citation statements)

References 140 publications

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“…Oxidative phosphorylation (OXPHOS) is one of the metabolic pathways sensitive to environmental toxicants [21]. Mitochondrial dysfunction can lead to increase in the partial reduction of oxygen by electrons leaking from the mitochondrial electron transport chain (ETC), generating an increase in reactive oxygen species (ROS) steady-state levels and, potentially, oxidative stress [22].…”

Section: Introductionmentioning

confidence: 99%

Acute Exposure to Permethrin Modulates Behavioral Functions, Redox, and Bioenergetics Parameters and Induces DNA Damage and Cell Death in Larval Zebrafish

Nunes

Schimith

Costa-Silva

et al. 2019

Oxidative Medicine and Cellular Longevity

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Permethrin (PM) is a synthetic pyrethroid insecticide widely used as domestic repellent. Damage effects to nontarget organisms have been reported, particularly in the early stages of development. Studies indicate redox unbalance as secondary PM effect. Therefore, our goal was to investigate the acute PM effects on larval zebrafish. Larvae (6 days postfertilization) were exposed to PM (25–600 μg/L) during 24 hours, and 50% lethal concentration was estimated. For subsequent assays, the sublethal PM concentrations of 25 and 50 μg/L were used. PM increased anxiety-like behaviors according to the Novel Tank and Light-Dark tests. At the molecular level, PM induced increased ROS, which may be related to the increased lipid peroxidation, DNA damage, and apoptosis detected in PM-exposed organisms. In parallel, upregulation of the antioxidant system was detected after PM exposure, with increased superoxide dismutase, glutathione S-transferase and glutathione reductase activities, and thiol levels. The increased of Nrf2 target genes and the activation of an electrophile response element-driven reporter Tg(EPRE:LUC-EGFP) suggest that the Nrf2 pathway can mediate a fast response to PM, leading to antioxidant amplification. By using high-resolution respirometry, we found that exposure to PM decreased the oxygen consumption in all respiratory stages, disrupting the oxidative phosphorylation and inhibiting the electron transfer system, leading to decrease in bioenergetics capacity. In addition, PM led to increases of residual oxygen consumption and changes in substrate control ratio. Glucose metabolism seems to be affected by PM, with increased lactate dehydrogenase and decreased citrate synthase activities. Taken together, our results demonstrated the adverse effects of acute sublethal PM concentrations during larval development in zebrafish, causing apparent mitochondrial dysfunction, indicating a potential mechanism to redox unbalance and oxidative stress, which may be linked to the detected cell death and alterations in normal behavior patterns caused by acute PM exposure.

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Section: Introductionmentioning

confidence: 99%

Acute Exposure to Permethrin Modulates Behavioral Functions, Redox, and Bioenergetics Parameters and Induces DNA Damage and Cell Death in Larval Zebrafish

Nunes

Schimith

Costa-Silva

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…However, the possibility of OXPHOS gene methylation within specific cells of the analysed animal species should not be excluded in certain circumstances. The oxidative phosphorylation system (OXPHOS) is a biochemical pathway located in the mitochondrial inner membrane responsible for energy production, apoptosis, and cell differentiation [31]. A proper OXPHOS function is important for cellular homeostasis, tissue dynamics, and health status of individuals [32].…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of CpG Sites and Islands Distributed in Mitochondrial DNA of Model Organisms

Kowal

Tkaczyk

Ząbek

et al. 2020

Animals

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The information about mtDNA methylation is still limited, thus epigenetic modification remains unclear. The lack of comprehensive information on the comparative epigenomics of mtDNA prompts comprehensive investigations of the epigenomic modification of mtDNA in different species. This is the first study in which the theoretical CpG localization in the mtDNA reference sequences from various species (12) was compared. The aim of the study was to determine the localization of CpG sites and islands in mtDNA of model organisms and to compare their distribution. The results are suitable for further investigations of mtDNA methylation. The analysis involved both strands of mtDNA sequences of animal model organisms representing different taxonomic groups of invertebrates and vertebrates. For each sequence, such parameters as the number, length, and localization of CpG islands were determined with the use of EMBOSS (European Molecular Biology Open Software Suite) software. The number of CpG sites for each sequence was indicated using the newcpgseek algorithm. The results showed that methylation of mtDNA in the analysed species involved mitochondrial gene expression. Our analyses showed that the CpG sites were commonly present in genomic regions including the D-loop, CYTB, ND6, ND5, ND4, ND3, ND2, ND1, COX3, COX2, COX1, ATP6, 16s rRNA, and 12s rRNA. The CpG distribution in animals from different species was diversified. Generally, the number of observed CpG sites of the mitochondrial genome was higher in the vertebrates than in the invertebrates. However, there was no relationship between the frequency of the CpG sites in the mitochondrial genome and the complexity of the analysed organisms. Interestingly, the distribution of the CpG sites for tRNA coding genes was usually cumulated in a larger CpG region in vertebrates. This paper may be a starting point for further research, since the collected information indicates possible methylation regions localized in mtDNA among different species including invertebrates and vertebrates.

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“…Our GO and KEGG analyses of Parkinson's disease SN gene expression data indicated enrichment of the BRAF-related genes in KEGG pathways such as oxidative phosphorylation and synaptic vesicle cycle, which have been implicated in the pathophysiology ofParkinson's disease[49,50]. Further exploring BRAF in Parkinson's disease-melanoma link in both in vitro and in vivo models may be important to better understand molecular mechanisms underlying this seemingly unusual link with potentials of repositioning BRAF targeting cancer drugs for the treatment of Parkinson's and other neurological diseases.…”

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confidence: 84%

Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK

Al-Kuwari

Srivast

et al. 2021

Preprint

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Background: Activating V600E in BRAF is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAF V600E has also been implicated in neurodegeneration. The present study aims to characterize BRAF V600E on cell death and survival in three major cell types of the CNS: neurons, astrocytes, and microglia. Methods : Multiple primary cultures and cell lines of glial cells and neurons were employed. BRAF V600E as well as BRAF WT expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors were achieved by siRNA. Gene expression data from patients with Parkinson’s disease was analyzed. Results : In astrocytes and microglia, BRAF V600E induces cell proliferation, and the proliferative effect in microglia is mediated by activated ERK but not JNK. Conditioned medium from BRAF V600E -expressing microglia induced neuronal cell death. In neuronal cells, BRAF V600E directly induces cell death, through JNK but not ERK. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease. Conclusions : Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity. It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.

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Prenatal exposure to oxidative phosphorylation xenobiotics and late-onset Parkinson disease

Cited by 13 publications

References 140 publications

Acute Exposure to Permethrin Modulates Behavioral Functions, Redox, and Bioenergetics Parameters and Induces DNA Damage and Cell Death in Larval Zebrafish

Acute Exposure to Permethrin Modulates Behavioral Functions, Redox, and Bioenergetics Parameters and Induces DNA Damage and Cell Death in Larval Zebrafish

Comparative Analysis of CpG Sites and Islands Distributed in Mitochondrial DNA of Model Organisms

Oncogenic BRAF V600E induces glial proliferation through ERK and neuronal death through JNK

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