scholarly journals Stress-induced phospho-ubiquitin formation causes parkin degradation

2018 ◽  
Author(s):  
Lyudmila Kovalchuke ◽  
Eugene V. Mosharov ◽  
Oren A. Levy ◽  
Lloyd A. Greene
Keyword(s):  
Oxidative Stress ◽  
Ubiquitin Ligase ◽  
Autosomal Recessive ◽  
Oxygen Species ◽  
Metabolic Dysfunction ◽  
Protein Levels ◽  
Sporadic Parkinson’S Disease ◽  
Stress Dependent ◽  
Dependent Pathway

Mutations in the E3 ubiquitin ligase parkin are the most common known cause of autosomal recessive parkinsonism. Multiple types of stress decrease parkin protein levels, an effect that may be relevant to sporadic Parkinson's disease (PD), but the mechanism(s) involved in this loss remain largely unclear. We sought to elucidate these mechanisms using a PD-relevant stressor, L-DOPA, the precursor to dopamine, which forms reactive oxygen species (ROS) as well as toxic quinones via auto-oxidation. We find that L-DOPA causes parkin loss through both an oxidative stress-independent and an oxidative stress-dependent pathway. Characterization of the latter reveals that it requires both the kinase PINK1 and parkin's interaction with phosphorylated ubiquitin (phospho-Ub) and is mediated by proteasomal degradation. Surprisingly, mitochondrial parkin activity and autoubiquitination as well as mitophagy are not required for such loss. During stress induced by the oxidative stressor hydrogen peroxide or the metabolic uncoupler CCCP, parkin degradation also requires its association with phospho-Ub, indicating that this mechanism is broadly generalizable. As oxidative stress, metabolic dysfunction and phospho-Ub levels are all elevated in PD patients, we suggest that these changes may lead to the loss of parkin expression in PD.

scholarly journals Oxidative stress–dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration

2015 ◽  
Vol 211 (4) ◽  
pp. 881-896 ◽  
Author(s):  
Shuji Wakatsuki ◽  
Akiko Furuno ◽  
Makiko Ohshima ◽  
Toshiyuki Araki
Keyword(s):  
Oxidative Stress ◽  
Ubiquitin Ligase ◽  
Wallerian Degeneration ◽  
Neuronal Apoptosis ◽  
Axonal Degeneration ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Growth Factor Receptor ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Ligase Activity ◽  
Stress Dependent

Oxidative stress is a well-known inducer of neuronal apoptosis and axonal degeneration. We previously showed that the E3 ubiquitin ligase ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B activation. We now demonstrate that oxidative stress serves as an activator of the ubiquitin ligase activity of ZNRF1 by inducing epidermal growth factor receptor (EGFR)–mediated phosphorylation at the 103rd tyrosine residue and that the up-regulation of ZNRF1 activity by oxidative stress leads to neuronal apoptosis and Wallerian degeneration. We also show that nicotinamide adenine dinucleotide phosphate–reduced oxidase activity is required for the EGFR-dependent phosphorylation-induced activation of ZNRF1 and resultant AKT degradation via the ubiquitin proteasome system to induce Wallerian degeneration. These results indicate the pathophysiological significance of the EGFR–ZNRF1 pathway induced by oxidative stress in the regulation of neuronal apoptosis and Wallerian degeneration. A deeper understanding of the regulatory mechanism for ZNRF1 catalytic activity via phosphorylation will provide a potential therapeutic avenue for neurodegeneration.

scholarly journals Separation and Characterization of Phenolamines and Flavonoids from Rape Bee Pollen, and Comparison of Their Antioxidant Activities and Protective Effects Against Oxidative Stress

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1264 ◽  
Author(s):  
Huifang Zhang ◽  
Rui Liu ◽  
Qun Lu
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Antioxidant Activities ◽  
Oxygen Species ◽  
Protective Effects ◽  
Antioxidant Power ◽  
Bee Pollen ◽  
Ferric Reducing Antioxidant Power ◽  
Kaempferol Glycosides

Phenolamines and flavonoids are two important components in bee pollen. There are many reports on the bioactivity of flavonoids in bee pollen, but few on phenolamines. This study aims to separate and characterize the flavonoids and phenolamines from rape bee pollen, and compare their antioxidant activities and protective effects against oxidative stress. The rape bee pollen was separated to obtain 35% and 50% fractions, which were characterized by HPLC-ESI-QTOF-MS/MS. The results showed that the compounds in 35% fraction were quercetin and kaempferol glycosides, while the compounds in 50% fraction were phenolamines, including di-p-coumaroyl spermidine, p-coumaroyl caffeoyl hydroxyferuloyl spermine, di-p-coumaroyl hydroxyferuloyl spermine, and tri-p-coumaroyl spermidine. The antioxidant activities of phenolamines and flavonoids were evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2’-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS), and ferric reducing antioxidant power (FRAP) assays. It was found that the antioxidant activity of phenolamines was significantly higher than that of flavonoids. Moreover, phenolamines showed better protective effects than flavonoids on HepG2 cells injured by AAPH. Furthermore, phenolamines could significantly reduce the reactive oxygen species (ROS), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and increase the superoxide dismutase (SOD) and glutathione (GSH) levels. This study lays a foundation for the further understanding of phenolamines in rape bee pollen.

scholarly journals High Potency of a Novel Resveratrol Derivative, 3,3′,4,4′-Tetrahydroxy-trans-stilbene, against Ovarian Cancer Is Associated with an Oxidative Stress-Mediated Imbalance between DNA Damage Accumulation and Repair

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Justyna Mikuła-Pietrasik ◽  
Patrycja Sosińska ◽  
Marek Murias ◽  
Marcin Wierzchowski ◽  
Marta Brewińska-Olchowik ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Ovarian Cancer ◽  
Dna Damage ◽  
P38 Mapk ◽  
Cancer Cell ◽  
Damage Accumulation ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Stress Dependent

We explored the effect of a new resveratrol (RVT) derivative, 3,3′,4,4′-tetrahydroxy-trans-stilbene (3,3′,4,4′-THS), on viability, apoptosis, proliferation, and senescence of three representative lines of ovarian cancer cells, that is, A2780, OVCAR-3, and SKOV-3,in vitro. In addition, the mechanistic aspects of 3,3′,4,4′-THS activity, including cell redox homeostasis (the production of reactive oxygen species, activity of enzymatic antioxidants, and magnitude of DNA damage accumulation and repair), and the activity of caspases (3, 8, and 9) and p38 MAPK were examined. The study showed that 3,3′,4,4′-THS affects cancer cell viability much more efficiently than its parent drug. This effect coincided with increased generation of reactive oxygen species, downregulated activity of superoxide dismutase and catalase, and excessive accumulation of 8-hydroxy-2′-deoxyguanosine and its insufficient repair due to decreased expression of DNA glycosylase I. Cytotoxicity elicited by 3,3′,4,4′-THS was related to increased incidence of apoptosis, which was mediated by caspases 3 and 9. Moreover, 3,3′,4,4′-THS inhibited cancer cell proliferation and accelerated senescence, which was accompanied by the activation of p38 MAPK. Collectively, our findings indicate that 3,3′,4,4′-THS may constitute a valuable tool in the fight against ovarian malignancy and that the anticancer capabilities of this stilbene proceed in an oxidative stress-dependent mechanism.

scholarly journals Alternative oxidase1a and 1d limit proline-dependent oxidative stress and aid salinity recovery in Arabidopsis

2021 ◽  
Author(s):  
Glenda Guek Khim Oh ◽  
Brendan M O'Leary ◽  
Santiago Signorelli ◽  
A. Harvey Millar
Keyword(s):  
Oxidative Stress ◽  
Consumption Rate ◽  
Oxygen Species ◽  
Mitochondrial Electron Transport Chain ◽  
Protein Levels ◽  
Respiration Rates ◽  
Transport Chain ◽  
Cytochrome Pathway ◽  
Species Production ◽  
Catalytic Capacity

A link between Pro catabolism and mitochondrial reactive oxygen species production has been established across eukaryotes and in plants increases in leaf respiration rates have been reported following Pro exposure. Here we investigated how alternative oxidases (AOXs) of the mitochondrial electron transport chain accommodate the large, atypical flux resulting from Pro catabolism and limit oxidative stress during Pro breakdown in mature Arabidopsis leaves. Following Pro treatment, AOX1a and AOX1d accumulate at transcript and protein levels, with AOX1d approaching the level of the typically dominant AOX1a isoform. We therefore sought to determine the function of both AOX isoforms under Pro respiring conditions. Oxygen consumption rate measurements in aox1a and aox1d leaves suggested these AOXs can functionally compensate for each other to establish enhanced AOX catalytic capacity in response to Pro. Generation of aox1a.aox1d lines showed complete loss of AOX proteins and activity upon Pro treatment, yet respiratory induction in response to Pro was still possible via the cytochrome pathway. However, aox1a.aox1d leaves suffered increased levels of oxidative stress and damage during Pro metabolism compared to WT or the single mutants. During recovery from salt stress, when high rates of Pro catabolism occur naturally, photosynthetic rates in aox1a.aox1d recovered slower than WT or the single aox lines, showing that both AOX1a and AOX1d are beneficial for cellular metabolism during Pro drawdown following osmotic stress. This work provides physiological evidence of a beneficial role for AOX1a but also the less studied AOX1d isoform in allowing safe catabolism of alternative respiratory substrates like Pro.

Characterization of the Protective Effect of Tetrahydrobiopterin Against S-Nitroso-N -Acetyl-D ,L-Penicillamine Induced Endothelial Cell Injury

Pteridines ◽  
1999 ◽  
Vol 10 (1) ◽  
pp. 14-19 ◽  
Author(s):  
Masakazu Ishii ◽  
Shunichi Shimizu ◽  
Kazutaka Momose ◽  
Yuji Kiuchi ◽  
Toshinori Yamamoto
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cell ◽  
Protective Effect ◽  
Cell Injury ◽  
Oxygen Species ◽  
No Donor ◽  
Endothelial Cell Injury ◽  
Ros Scavenger ◽  
Intracellular Oxidative Stress

The purpose of this study was to characterize the protective effect of tetrahydrobiopterin (BH4), one of the cofactors of nitric oxide (NO) synthase, against NO-induced endothelial cell injury. The addition of S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a NO donor, to endothelial cells induced the release of lactate dehydrogenase (LDH), a marker for cell injury. The SNAP-induced endothelial cell injury was markedly reduced by pretreatment with sepiapterin, a precursor of BH4 synthesis. On the other hand, exogenous BH4 had little effect on the SNAP-induced endothelial cell injury. We recently found that NO-induced endothelial cell injury involves a part of H202 production, since the injury was blocked by the treatment with catalase. Although BH4 released reactive oxygen species (ROS) in cell-free conditions, the increase in intracellular BH4 by pretreatment with sepiapterin strongly reduced H202-induced intracellular oxidative stress. These findings suggest that the increase in intracellular BH4 content but not extracellular BH4, strongly attenuates NO-induced endothelial cell injury by at least one of the mechanisms by which BH4 reduces H202-induced oxidative stress. Intracellular BH4 seems mainly to play a role as an antioxidant or as a ROS-scavenger.

scholarly journals The p66Shc protein controls redox signaling and oxidation-dependent DNA damage in human liver cells

2015 ◽  
Vol 309 (10) ◽  
pp. G826-G840 ◽  
Author(s):  
Sebastio Perrini ◽  
Federica Tortosa ◽  
Annalisa Natalicchio ◽  
Consiglia Pacelli ◽  
Angelo Cignarelli ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Hepg2 Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Protein Levels ◽  
Human Liver Cells ◽  
Alcoholic Steatohepatitis ◽  
Liver Biopsies

The p66Shc protein mediates oxidative stress-related injury in multiple tissues. Steatohepatitis is characterized by enhanced oxidative stress-mediated cell damage. The role of p66Shc in redox signaling was investigated in human liver cells and alcoholic steatohepatitis. HepG2 cells with overexpression of wild-type or mutant p66Shc, with Ser36 replacement by Ala, were obtained through infection with recombinant adenoviruses. Reactive oxygen species and oxidation-dependent DNA damage were assessed by measuring dihydroethidium oxidation and 8-hydroxy-2′-deoxyguanosine accumulation into DNA, respectively. mRNA and protein levels of signaling intermediates were evaluated in HepG2 cells and liver biopsies from control and alcoholic steatohepatitis subjects. Exposure to H2O2 increased reactive oxygen species and phosphorylation of p66Shc on Ser36 in HepG2 cells. Overexpression of p66Shc promoted reactive oxygen species synthesis and oxidation-dependent DNA damage, which were further enhanced by H2O2. p66Shc activation also resulted in increased Erk-1/2, Akt, and FoxO3a phosphorylation. Blocking of Erk-1/2 activation inhibited p66Shc phosphorylation on Ser36. Increased p66Shc expression was associated with reduced mRNA levels of antioxidant molecules, such as NF-E2-related factor 2 and its target genes. In contrast, overexpression of the phosphorylation defective p66Shc Ala36 mutant inhibited p66Shc signaling, enhanced antioxidant genes, and suppressed reactive oxygen species and oxidation-dependent DNA damage. Increased p66Shc protein levels and Akt phosphorylation were observed in liver biopsies from alcoholic steatohepatitis compared with control subjects. In human alcoholic steatohepatitis, increased hepatocyte p66Shc protein levels may enhance susceptibility to DNA damage by oxidative stress by promoting reactive oxygen species synthesis and repressing antioxidant pathways.

SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging

2012 ◽  
Vol 444 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Albert Giralt ◽  
Francesc Villarroya
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Energy Metabolism ◽  
Reactive Oxygen ◽  
Acetate Metabolism ◽  
Oxygen Species ◽  
Neural Degeneration ◽  
The Metabolic Syndrome ◽  
Brown Adipose ◽  
Stress Dependent

SIRT3 is a member of the sirtuin family of protein deacetylases that is preferentially localized to mitochondria. Prominent among the proteins targeted by SIRT3 are enzymes involved in energy metabolism processes, including the respiratory chain, tricarboxylic acid cycle, fatty acid β-oxidation and ketogenesis. Through these actions, SIRT3 controls the flow of mitochondrial oxidative pathways and, consequently, the rate of production of reactive oxygen species. In addition, SIRT3-mediated deacetylation activates enzymes responsible for quenching reactive oxygen species, and thereby exerts a profound protective action against oxidative stress-dependent pathologies, such as cardiac hypertrophy and neural degeneration. SIRT3 also plays a role in multiple additional metabolic processes, from acetate metabolism to brown adipose tissue thermogenesis, often by controlling mitochondrial pathways through the deacetylation of target enzymes. In general, SIRT3 activity and subsequent control of enzymes involved in energy metabolism is consistent with an overall role of protecting against age-related diseases. In fact, experimental and genetic evidence has linked SIRT3 activity with increased lifespan. In the coming years, the identification of drugs and nutrients capable of increasing SIRT3 expression or modulating SIRT3 activity can be expected to provide promising strategies for ameliorating the metabolic syndrome and other oxidative stress-related diseases that appear preferentially with aging, such as cancer, cardiac dysfunction and neural degeneration.

scholarly journals N-acetylcysteine alleviates PCB52-induced hepatotoxicity by repressing oxidative stress and inflammatory responses

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9720
Author(s):  
Wen-Tao Zhou ◽  
Li-Bin Wang ◽  
Hao Yu ◽  
Kai-Kai Zhang ◽  
Li-Jian Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Inflammatory Responses ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Nrf2 Pathway ◽  
Protein Levels ◽  
Saline Pretreatment

Polychlorinated biphenyls (PCBs), particularly low chlorinated congeners in our environment, can induce human hepatotoxicity. However, the mechanisms by which PCBs cause hepatotoxicity remain elusive. Moreover, there are no effective treatments for this condition. In this study, 40 μM PCB52 was administered to rat (Brl-3A) and human hepatocytes (L-02) for 48 h following the N-acetylcysteine (NAC)/saline pretreatment. A significant decrease in cell viability was observed in PCB52-treated cells relative to the control. Besides, PCB52 significantly increased reactive oxygen species (ROS) levels and malondialdehyde (MDA) contents, suggesting induction of oxidative stress. The expression of Traf6, MyD88, and Tnf in Brl-3A cells and that of MYD88, TNF, and IL1B in L-02 cells were significantly upregulated by PCB52. Consistently, overexpression of TLR4, MyD88, Traf6, and NF-κB p65 proteins was observed in PCB52-treated cells, indicating activation of inflammatory responses. Nevertheless, no changes in kelch-like ECH-associated protein 1 (keap1), nuclear factor-erythroid 2-related factor (nrf2), and heme oxygenase-1 proteins were observed in PCB52-treated cells, indicating non-activation of the keap1/nrf2 pathway. Pretreatment with NAC significantly ameliorated PCB52 effects on cell viability, ROS levels, MDA contents and expression of inflammatory elements at both RNA and protein levels. However, no changes in keap1, nrf2 and HO-1 protein levels were detected following NAC pretreatment. Taken together, with non-activated keap1/nrf2 pathway, PCB52-induced oxidative stress and inflammatory responses could be responsible for its hepatotoxicity. These effects were effectively attenuated by NAC pretreatment, which scavenges ROS and dampens inflammatory responses. This study might provide novel strategies for the treatment of the PCBs-associated hepatotoxic effects.

Characterization of oxidative stress status by evaluation of reactive oxygen species levels in whole semen and isolated spermatozoa

2005 ◽  
Vol 83 (3) ◽  
pp. 800-803 ◽  
Author(s):  
Shyam S.R. Allamaneni ◽  
Ashok Agarwal ◽  
Kiran P. Nallella ◽  
Rakesh K. Sharma ◽  
Anthony J. Thomas ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Oxidative Stress Status

Abstract 449: GRK2-S670A Mice Reveal Cardioprotection Post Ischemia-reperfusion

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Priscila Y Sato ◽  
J K Chuprun ◽  
Christopher J Traynham ◽  
Anna Maria Lucchese ◽  
Ancai Yuan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemia Reperfusion ◽  
Cardiac Contractility ◽  
Pharmacological Interventions ◽  
Area At Risk ◽  
Protein Levels ◽  
Β Adrenergic Receptors ◽  
G Protein Coupled

β-adrenergic receptors (βARs) are critical regulators of cardiac contractility whose function are drastically impaired during heart failure (HF). Activated βARs are regulated via phosphorylation by G-protein coupled receptor kinase-2 (GRK2) and subsequent interaction with β-arrestin. Numerous studies have shown that GRK2 is elevated in human HF and animal models demonstrate that it contributes to HF pathogenesis after ischemic injury (IR). Further, our lab has uncovered non-canonical actions of GRK2 that are involved in HF development. One such novel action of GRK2 is within mitochondria where we have shown increased GRK2 localization after oxidative stress. Our lab has shown that in the heart, phosphorylation of GRK2 via Map kinase at residue Ser670 promotes binding to Hsp90 and further enhances translocation of GRK2 to the mitochondria after oxidative stress such as ischemia. To determine the ultimate role of this pathway in the post-ischemic heart we have generated novel GRK2-S670A mice where all endogenous GRK2 cannot be phosphorylated at this residue. Baseline characterization of these mice along with their controls, show a minimal phenotype, however we have found significant differences post-IR. Compared to control mice (NLC), GRK2-S670A have significantly less infarction size 24 hrs after IR and echocardiography and hemodynamics revealed significantly improved cardiac function in GRK2-S670A mice post-IR. GRK2-S670A mice showed improved ejection fraction (52.83%+/- 2.826 S670A vs 42.38%+/- 1.603 NLC) and smaller infarcted areas (9.942%+/- 1.763 S670A vs 20.78%+/- 3.579 NLC) when compared to NLC mice. Further, we found that mitochondrial GRK2 protein levels were lower in the GRK2-S670A mice at the area at risk (0.1428+/-0.02485 S670A vs 0.2327+/- 0.023 NLC). Overall, our data suggest that phosphorylation at Ser670 of GRK2 might act as a “biological switch” in cardiomyocytes, where un-phosphorylated GRK2 is readily available in the cytoplasm to desensitize receptors such as βARs, but upon phosphorylation, GRK2 translocates to the mitochondria leading to detrimental effects including cell death. This mechanism suggests a novel way to develop pharmacological interventions to aid in the treatment of HF.

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