One Week of CDAHFD Induces Steatohepatitis and Mitochondrial Dysfunction with Oxidative Stress in Liver.
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ABSTRACT:
SUBMITTER: Sugasawa T
PROVIDER: S-EPMC8198552 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:How retinal pigmented epithelial (RPE) cells degenerate from oxidative stress in age-related macular degeneration (AMD) is incompletely understood. The study's intent was to identify key cytoprotective pathways activated by oxidative stress, and to determine the extent of their protection. Immunohistochemistry was used to identify the unfolded protein response (UPR) and mitochondria in the RPE of AMD samples. Maculas with early AMD had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling in mildly degenerated RPE. RPE cells treated with cigarette smoke extract (CSE), by microarray analysis, had over-represented genes involved in the antioxidant and unfolded protein response, and mitochondrial location. CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, which activated CHOP. CHOP knockdown compromised cell viability after CSE exposure. At the same CSE doses, mitochondria generated superoxide anion and produced less ATP. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP, which elicited RPE epithelial-mesenchymal transition, as suggested by altered ZO1 immunolabeling of RPE flatmounts. Our experiments indicate that RPE cells exposed to oxidative stress respond with a cytoprotective antioxidant and unfolded protein response, but develop mitochondrial impairment that contributed to epithelial mesenchymal transition. With similar responses in the RPE of early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress while the ER elicits a protective response during early AMD. A total of 9 samples were analyzed: 3 control samples, 3 samples treated with 100ug/ml of Cigarette Smoke Condensate, and 3 samples treated with 250ug/ml of Cigarettes Smoke Condensate.
2014-01-30 | E-GEOD-49107 | biostudies-arrayexpress
Project description:There is an increasing recognition that mitochondrial dysfunction is associated with autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction and how mitochondrial abnormalities might interact with other physiological disturbances such as oxidative stress. Reserve capacity is a measure of the ability of the mitochondria to respond to physiological stress. In this study, we demonstrate, for the first time, that lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) have an abnormal mitochondrial reserve capacity before and after exposure to reactive oxygen species (ROS). Ten (44%) of 22 AD LCLs exhibited abnormally high reserve capacity at baseline and a sharp depletion of reserve capacity when challenged with ROS. This depletion of reserve capacity was found to be directly related to an atypical simultaneous increase in both proton-leak respiration and adenosine triphosphate-linked respiration in response to increased ROS in this AD LCL subgroup. In this AD LCL subgroup, 48-hour pretreatment with N-acetylcysteine, a glutathione precursor, prevented these abnormalities and improved glutathione metabolism, suggesting a role for altered glutathione metabolism associated with this type of mitochondrial dysfunction. The results of this study suggest that a significant subgroup of AD children may have alterations in mitochondrial function, which could render them more vulnerable to a pro-oxidant microenvironment as well as intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxins. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors.
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Project description:Background:Environmental pollution induces oxidative stress and apoptosis in mammalian oocytes, which can cause defects in reproduction; however, the molecular regulation of oxidative stress in oocytes is still largely unknown. In the present study, we identified that dynamin-related protein 1 (DRP1) is an important molecule regulating oocyte mitochondrial function and preventing oxidative stress/apoptosis. DRP1 is a member of the dynamin GTPase superfamily localized at the mitochondrial-endoplasmic reticulum interaction site, where it regulates the fission of mitochondria and other related cellular processes. Results:Our results show that DRP1 was stably expressed during different stages of porcine oocyte meiosis, and might have a potential relationship with mitochondria as it exhibited similar localization. Loss of DRP1 activity caused failed porcine oocyte maturation and cumulus cell expansion, as well as defects in polar body extrusion. Further analysis indicated that a DRP1 deficiency caused mitochondrial dysfunction and induced oxidative stress, which was confirmed by increased reactive oxygen species levels. Moreover, the incidence of early apoptosis increased as detected by positive Annexin-V signaling. Conclusions:Taken together, our results indicate that DRP1 is essential for porcine oocyte maturation and that a DRP1 deficiency could induce mitochondrial dysfunction, oxidative stress, and apoptosis.
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Project description:How cells degenerate from oxidative stress in aging-related disease is incompletely understood. This study's intent was to identify key cytoprotective pathways activated by oxidative stress and determine the extent of their protection. Using an unbiased strategy with microarray analysis, we found that retinal pigmented epithelial (RPE) cells treated with cigarette smoke extract (CSE) had overrepresented genes involved in the antioxidant and unfolded protein response (UPR). Differentially expressed antioxidant genes were predominantly located in the cytoplasm, with no induction of genes that neutralize superoxide and H2O2 in the mitochondria, resulting in accumulation of superoxide and decreased ATP production. Simultaneously, CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, including CHOP, which was cytoprotective because CHOP knockdown decreased cell viability. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP and developed epithelial-mesenchymal transition, as suggested by decreased LRAT abundance, altered ZO-1 immunolabeling, and dysmorphic cell shape. Mildly degenerated RPE from early age-related macular degeneration (AMD) samples had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling. Although oxidative stress is thought to induce an antioxidant response with cooperation between the mitochondria and the ER, herein we show that mitochondria become impaired sufficiently to induce epithelial-mesenchymal transition despite a protective UPR. With similar responses in early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress despite a protective UPR during the early phases of aging-related disease.
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Project description:Homocysteine (Hcy) has been shown to have a neurotoxic effect on ischemic brain cells; however, the underlying mechanisms remain incompletely understood. Here, we examined whether Hcy treatment influences mitochondria injury, oxidative stress, and mitochondrial STAT3 (mitoStat3) expression in rat ischemic brain. Our results demonstrated that Hcy treatment aggravated the damage of mitochondrial ultrastructure in the brain cortex and the dentate gyrus region of the hippocampus after focal cerebral ischemia. An elevated Hcy level was also accompanied by the significant inhibition of mitochondrial complex I-III enzymatic activities in addition to an increase in cytochrome c release. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) content and mitoStat3 protein phosphorylation level were increased in Hcy-treated animals, whereas AG490, a Jak2 inhibitor, inhibited mitoStat3 phosphorylation as well as 8-OHdG levels induced by Hcy. In vitro studies revealed that Hcy also markedly increased reactive oxygen species (ROS) and mitoStat3 levels. In addition, the inhibition of pSTAT3 reduced Hcy-mediated increase in ROS levels, whereas quenching ROS using the ROS inhibitor glutathione ethyl ester inhibited Hcy-mediated pSTAT3 overactivation in Neuro2a cells. These findings suggest that the development of therapies that interfere with the ROS/pSTAT3 pathway may be helpful for treating cerebral infarction-related diseases associated with Hcy.
| S-EPMC5537278 | biostudies-literature
Project description:Mitochondrial DNA (mtDNA) is located in close proximity of the respiratory chains, which are the main cellular source of reactive oxygen species (ROS). ROS can induce oxidative base lesions in mtDNA and are believed to be an important cause of the mtDNA mutations, which accumulate with aging and in diseased states. However, recent studies indicate that cumulative levels of base substitutions in mtDNA can be very low even in old individuals. Considering the reduced complement of DNA repair pathways available in mitochondria and higher susceptibility of mtDNA to oxidative damage than nDNA, it is presently unclear how mitochondria manage to maintain the integrity of their genetic information in the face of the permanent exposure to ROS. Here we show that oxidative stress can lead to the degradation of mtDNA and that strand breaks and abasic sites prevail over mutagenic base lesions in ROS-damaged mtDNA. Furthermore, we found that inhibition of base excision repair enhanced mtDNA degradation in response to both oxidative and alkylating damage. These observations suggest a novel mechanism for the protection of mtDNA against oxidative insults whereby a higher incidence of lesions to the sugar-phosphate backbone induces degradation of damaged mtDNA and prevents the accumulation of mutagenic base lesions.
| S-EPMC2677867 | biostudies-other
Project description:How retinal pigmented epithelial (RPE) cells degenerate from oxidative stress in age-related macular degeneration (AMD) is incompletely understood. The study's intent was to identify key cytoprotective pathways activated by oxidative stress, and to determine the extent of their protection. Immunohistochemistry was used to identify the unfolded protein response (UPR) and mitochondria in the RPE of AMD samples. Maculas with early AMD had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling in mildly degenerated RPE. RPE cells treated with cigarette smoke extract (CSE), by microarray analysis, had over-represented genes involved in the antioxidant and unfolded protein response, and mitochondrial location. CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, which activated CHOP. CHOP knockdown compromised cell viability after CSE exposure. At the same CSE doses, mitochondria generated superoxide anion and produced less ATP. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP, which elicited RPE epithelial-mesenchymal transition, as suggested by altered ZO1 immunolabeling of RPE flatmounts. Our experiments indicate that RPE cells exposed to oxidative stress respond with a cytoprotective antioxidant and unfolded protein response, but develop mitochondrial impairment that contributed to epithelial mesenchymal transition. With similar responses in the RPE of early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress while the ER elicits a protective response during early AMD.
2014-01-30 | GSE49107 | GEO
Project description:BackgroundKindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. In spite of the knowledge underlying cause of this disease involving mutations of FERMT1 (fermitin family member 1), and efforts to characterize genotype-phenotype correlations, the clinical variability of this genodermatosis is still poorly understood. In addition, several pathognomonic features of KS, not related to skin fragility such as aging, inflammation and cancer predisposition have been strongly associated with oxidative stress. Alterations of the cellular redox status have not been previously studied in KS. Here we explored the role of oxidative stress in the pathogenesis of this rare cutaneous disease.MethodsPatient-derived keratinocytes and their respective controls were cultured and classified according to their different mutations by PCR and western blot, the oxidative stress biomarkers were analyzed by spectrophotometry and qPCR and additionally redox biosensors experiments were also performed. The mitochondrial structure and functionality were analyzed by confocal microscopy and electron microscopy.ResultsPatient-derived keratinocytes showed altered levels of several oxidative stress biomarkers including MDA (malondialdehyde), GSSG/GSH ratio (oxidized and reduced glutathione) and GCL (gamma-glutamyl cysteine ligase) subunits. Electron microscopy analysis of both, KS skin biopsies and keratinocytes showed marked morphological mitochondrial abnormalities. Consistently, confocal microscopy studies of mitochondrial fluorescent probes confirmed the mitochondrial derangement. Imbalance of oxidative stress biomarkers together with abnormalities in the mitochondrial network and function are consistent with a pro-oxidant state.ConclusionsThis is the first study to describe mitochondrial dysfunction and oxidative stress involvement in KS.
| S-EPMC4302591 | biostudies-literature
Project description:ObjectiveAir pollution is associated with increased cardiovascular morbidity and mortality, as well as dyslipidemia and metabolic syndrome. Our goal was to dissect the mechanisms involved. Approach and Results: We assessed the effects of exposure to air pollution on lipid metabolism in mice through assessment of plasma lipids and lipoproteins, oxidized fatty acids 9-HODE (9-hydroxyoctadecadienoic) and 13-HODE (13-hydroxyoctadecadienoic), lipid, and carbohydrate metabolism. Findings were corroborated, and mechanisms were further assessed in HepG2 hepatocytes in culture. ApoE knockout mice exposed to inhaled diesel exhaust (DE, 6 h/d, 5 days/wk for 16 weeks) exhibited elevated plasma cholesterol and triglyceride levels, increased hepatic triglyceride content, and higher hepatic levels of 9-HODE and 13-HODE, as compared to control mice exposed to filtered air. A direct effect of DE exposure on hepatocytes was demonstrated by treatment of HepG2 cells with a methanol extract of DE particles followed by loading with oleic acid. As observed in vivo, this led to increased triglyceride content and significant downregulation of ACAD9 mRNA expression. Treatment of HepG2 cells with DE particles and oleic acid did not alter de novo lipogenesis but inhibited total, mitochondrial, and ATP-linked oxygen consumption rate, indicative of mitochondrial dysfunction. Treatment of isolated mitochondria, prepared from mouse liver, with DE particles and oleic acid also inhibited mitochondrial complex activity and β-oxidation.ConclusionsDE exposure leads to dyslipidemia and liver steatosis in ApoE knockout mice, likely due to mitochondrial dysfunction and decreased lipid catabolism.
| S-EPMC6703953 | biostudies-literature