scholarly journals The mitochondrial copper chaperone COX11 plays an auxiliary role in the defence against oxidative stress

2018 ◽  
Author(s):  
Ivan Radin ◽  
Uta Gey ◽  
Luise Kost ◽  
Iris Steinebrunner ◽  
Gerhard Rödel
Keyword(s):  
Oxidative Stress ◽  
Underlying Mechanism ◽  
Copper Chaperone ◽  
Unexpected Result ◽  
Wild Type ◽  
Inner Mitochondrial Membrane ◽  
Yeast Strains ◽  
Redox Capacity ◽  
Stress Relieving ◽  
Ros Scavenger

AbstractCOX11, a protein anchored in the inner mitochondrial membrane, was originally identified as a copper chaperone delivering Cu+ to the cytochrome c oxidase of the respiratory chain. Here, we present evidence that this protein is also involved in the defence against reactive oxygen species. Quantitative PCR analyses in the model plant Arabidopsis thaliana revealed that the level of AtCOX11 mRNA rises under oxidative stress. The unexpected result that AtCOX11 knock-down lines contained less ROS than the wild-type can possibly be explained by the impaired oxidative phosphorylation, resulting in less respiration-dependent ROS formation. Similarly, we observed that yeast Saccharomyces cerevisiae ScCOX11 null mutants produced less ROS than wild-type cells. However, when exposed to oxidative stress, yeast strains overexpressing ScCOX11 or AtCOX11 showed lower ROS levels compared with the control indicating a ROS-detoxifying effect of the COX11 proteins. The additive effect on ROS sensitivity upon deletion of ScCOX11 in addition to the known ROS scavenger gene SOD1 encoding superoxide dismutase 1 corroborates the oxidative stress-relieving function of ScCOX11. Moreover, yeast strains overexpressing soluble versions of either AtCOX11 or ScCOX11 became more resistant against oxidative stress. The importance of three conserved cysteines for the ROS scavenger function became apparent after their deletion that resulted in the loss of ROS resistance. Further studies of strains producing COX11 proteins with individually mutated cysteines indicate that the formation of disulphide bridges might be the underlying mechanism responsible for the antioxidative activity of COX11 proteins. Both AtCOX11 and ScCOX11 apparently partake in oxidative stress defence by directly or indirectly exploiting the redox capacity of their cysteine residues.

scholarly journals Neuronal-specific function of hTim8a in Complex IV assembly provides insight into the molecular mechanism underlying Mohr-Tranebjærg syndrome

2019 ◽  
Author(s):  
Yilin Kang ◽  
Alexander J. Anderson ◽  
David P. De Souza ◽  
Catherine S. Palmer ◽  
Kenji M. Fujihara ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disease ◽  
Neuronal Cells ◽  
Underlying Mechanism ◽  
Copper Chaperone ◽  
Intermembrane Space ◽  
Specific Function ◽  
Hydrophobic Membrane ◽  
Complex Iv ◽  
Enhanced Sensitivity

AbstractHuman Tim8a is a member of an intermembrane space chaperone network, known as the small TIM family, which transport hydrophobic membrane proteins through this compartment. Mutations in TIMM8A cause a neurodegenerative disease, Mohr-Tranebjærg syndrome (MTS), which is characterised by sensorineural hearing loss, dystonia and blindness. Nothing is known about the function of hTim8a in neuronal cells and consequently how lack of hTim8a leads to a neurodegenerative disease. We identified a novel cell-specific function of hTim8a in the assembly of Complex IV, which is mediated through a transient interaction with the copper chaperone COX17. Complex IV assembly defects in cells lacking hTim8a leads to oxidative stress and changes to key apoptotic regulators, including cytochrome c and Bax, which primes cells for cell death. Alleviation of oxidative stress using Vitamin E rescues cells from apoptotic vulnerability. We hypothesis that enhanced sensitivity of neuronal cells to apoptosis is the underlying mechanism of MTS.

Abstract 628: Pro-Apoptotic Bnip3 Functions as a Mitochondrial Sensor of Oxidative Stress in Myocardial Ischemia/Reperfusion

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Dieter A Kubli ◽  
Melissa N Quinsay ◽  
Asa B Gustafsson
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Disulfide Bonds ◽  
Ischemia Reperfusion ◽  
Wild Type ◽  
Redox Sensor ◽  
Sds Page ◽  
Ros Scavenger ◽  
Tm Domain ◽  
Myocardial Ischemia Reperfusion

Bnip3 is a member of the BH3-only subfamily of pro-apoptotic Bcl-2 proteins and is associated with mitochondrial dysfunction and cell death in the myocardium. We previously found that Bnip3 contributes to ischemia/reperfusion (I/R) injury, but it is not known how I/R causes activation of Bnip3. We have investigated potential mechanism(s) by which Bnip3 activity is regulated. Western blot analysis of heart lysates revealed that Bnip3 forms a ∼48 kDa complex after I/R that is sensitive to reduction by DTT. Complex formation was reduced when hearts were perfused with the reactive oxygen species (ROS) scavenger N-acetyl cysteine prior to I/R. The complex also increased in isolated myocytes treated with hydrogen peroxide, suggesting that the DTT-sensitive complex is formed by increased oxidative stress. To further investigate the function of this complex, we overexpressed Bnip3 in HL-1 myocytes and found that most of Bnip3 existed in the 48-kDa complex which correlated with increased cell death. In contrast, endogenous Bnip3 in the heart exists mainly as a monomer under normal conditions. Scanning of the Bnip3 protein sequence revealed a single conserved Cys residue at position 64, which may be susceptible to oxidation. Mutation of the Cys to an Ala or deletion of the N-term (aa 1–64) resulted in reduced cell death activity of Bnip3 compared to wild type when overexpressed in HL-1 myocytes. Separation of purified Bnip3 on SDS-PAGE showed the presence of the same DTT sensitive complex, suggesting that the complex is a Bnip3 homodimer. The transmembrane (TM) domain of Bnip3 has previously been identified to be important for homodimerization, and contains a His residue at position 173 that is essential for homodimerization. Mutation of the His to an Ala also resulted in reduced cell death activity of Bnip3 compared to wild type when overexpressed in HL-1 myocytes, suggesting that homodimerization is important for cell death activity of Bnip3. A consequence of I/R is the production of ROS and oxidation of proteins, which promotes formation of Cys disulfide bonds between proteins. Thus, these studies suggest that Bnip3 functions as a redox sensor in cells where increased oxidative stress induces homodimerization of Bnip3 via N-terminal Cys residue and the C-terminal TM domain.

scholarly journals NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice

2018 ◽  
Vol 236 (1) ◽  
pp. 13-28 ◽  
Author(s):  
E Meimaridou ◽  
M Goldsworthy ◽  
V Chortis ◽  
E Fragouli ◽  
P A Foster ◽  
...  
Keyword(s):  
Redox Homeostasis ◽  
Redox Balance ◽  
Underlying Mechanism ◽  
Rna Seq ◽  
Wild Type ◽  
Inner Mitochondrial Membrane ◽  
Steroidogenic Enzyme ◽  
High Concentrations ◽  
Glucocorticoid Deficiency ◽  
Bac Transgenic Mice

Nicotinamide nucleotide transhydrogenase, NNT, is a ubiquitous protein of the inner mitochondrial membrane with a key role in mitochondrial redox balance. NNT produces high concentrations of NADPH for detoxification of reactive oxygen species by glutathione and thioredoxin pathways. In humans, NNT dysfunction leads to an adrenal-specific disorder, glucocorticoid deficiency. Certain substrains of C57BL/6 mice contain a spontaneously occurring inactivating Nnt mutation and display glucocorticoid deficiency along with glucose intolerance and reduced insulin secretion. To understand the underlying mechanism(s) behind the glucocorticoid deficiency, we performed comprehensive RNA-seq on adrenals from wild-type (C57BL/6N), mutant (C57BL/6J) and BAC transgenic mice overexpressing Nnt (C57BL/6JBAC). The following results were obtained. Our data suggest that Nnt deletion (or overexpression) reduces adrenal steroidogenic output by decreasing the expression of crucial, mitochondrial antioxidant (Prdx3 and Txnrd2) and steroidogenic (Cyp11a1) enzymes. Pathway analysis also revealed upregulation of heat shock protein machinery and haemoglobins possibly in response to the oxidative stress initiated by NNT ablation. In conclusion, using transcriptomic profiling in adrenals from three mouse models, we showed that disturbances in adrenal redox homeostasis are mediated not only by under expression of NNT but also by its overexpression. Further, we demonstrated that both under expression or overexpression of NNT reduced corticosterone output implying a central role for it in the control of steroidogenesis. This is likely due to a reduction in the expression of a key steroidogenic enzyme, Cyp11a1, which mirrored the reduction in corticosterone output.

scholarly journals Alkaline Ceramidase Mediates the Oxidative Stress Response in Drosophila melanogaster Through Sphingosine

2019 ◽  
Vol 19 (3) ◽  
Author(s):  
Chun-Hong Zhang ◽  
Min-Jing Zhang ◽  
Xiao-Xiao Shi ◽  
Cungui Mao ◽  
Zeng-Rong Zhu
Keyword(s):  
Oxidative Stress ◽  
Drosophila Melanogaster ◽  
Stress Resistance ◽  
Antioxidative Activity ◽  
Underlying Mechanism ◽  
Oxidative Stress Response ◽  
Differentially Expressed Proteins ◽  
Wild Type ◽  
Transcription Level ◽  
Insight Into

Abstract Alkaline ceramidase (Dacer) in Drosophila melanogaster was demonstrated to be resistant to paraquat-induced oxidative stress. However, the underlying mechanism for this resistance remained unclear. Here, we showed that sphingosine feeding triggered the accumulation of hydrogen peroxide (H2O2). Dacer-deficient D. melanogaster (Dacer mutant) has higher catalase (CAT) activity and CAT transcription level, leading to higher resistance to oxidative stress induced by paraquat. By performing a quantitative proteomic analysis, we identified 79 differentially expressed proteins in comparing Dacer mutant to wild type. Three oxidoreductases, including two cytochrome P450 (CG3050, CG9438) and an oxoglutarate/iron-dependent dioxygenase (CG17807), were most significantly upregulated in Dacer mutant. We presumed that altered antioxidative activity in Dacer mutant might be responsible for increased oxidative stress resistance. Our work provides a novel insight into the oxidative antistress response in D. melanogaster.

scholarly journals Function of hTim8a in complex IV assembly in neuronal cells provides insight into pathomechanism underlying Mohr-Tranebjærg syndrome

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Yilin Kang ◽  
Alexander J Anderson ◽  
Thomas Daniel Jackson ◽  
Catherine S Palmer ◽  
David P De Souza ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disease ◽  
Neuronal Cells ◽  
Underlying Mechanism ◽  
Copper Chaperone ◽  
Intermembrane Space ◽  
Complex Iv ◽  
Enhanced Sensitivity ◽  
Chaperone Network ◽  
Insight Into

Human Tim8a and Tim8b are members of an intermembrane space chaperone network, known as the small TIM family. Mutations in TIMM8A cause a neurodegenerative disease, Mohr-Tranebjærg syndrome (MTS), which is characterised by sensorineural hearing loss, dystonia and blindness. Nothing is known about the function of hTim8a in neuronal cells or how mutation of this protein leads to a neurodegenerative disease. We show that hTim8a is required for the assembly of Complex IV in neurons, which is mediated through a transient interaction with Complex IV assembly factors, in particular the copper chaperone COX17. Complex IV assembly defects resulting from loss of hTim8a leads to oxidative stress and changes to key apoptotic regulators, including cytochrome c, which primes cells for death. Alleviation of oxidative stress with Vitamin E treatment rescues cells from apoptotic vulnerability. We hypothesise that enhanced sensitivity of neuronal cells to apoptosis is the underlying mechanism of MTS.

scholarly journals Glyoxalase I disruption and external carbonyl stress impair mitochondrial function in human induced pluripotent stem cells and derived neurons

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomonori Hara ◽  
Manabu Toyoshima ◽  
Yasuko Hisano ◽  
Shabeesh Balan ◽  
Yoshimi Iwayama ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Caspase 3 ◽  
Intervention Strategy ◽  
Underlying Mechanism ◽  
Carbonyl Stress ◽  
Gene Encoding ◽  
Induced Pluripotent

AbstractCarbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, we found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger. Our observations can be used for designing an intervention strategy for diseases, particularly those induced by enhanced carbonyl stress or oxidative stress.

scholarly journals Transcriptome Analysis Provides Insights into the Mechanism of Astaxanthin Enrichment in a Mutant of the Ridgetail White Prawn Exopalaemon carinicauda

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 618
Author(s):  
Yue Jin ◽  
Shihao Li ◽  
Yang Yu ◽  
Chengsong Zhang ◽  
Xiaojun Zhang ◽  
...  
Keyword(s):  
Transcriptome Analysis ◽  
Underlying Mechanism ◽  
Biological Processes ◽  
Wild Type ◽  
Expression Levels ◽  
In The Wild ◽  
Cuticle Proteins ◽  
Apolipoprotein D ◽  
High Level ◽  
Lower Expression

A mutant of the ridgetail white prawn, which exhibited rare orange-red body color with a higher level of free astaxanthin (ASTX) concentration than that in the wild-type prawn, was obtained in our lab. In order to understand the underlying mechanism for the existence of a high level of free astaxanthin, transcriptome analysis was performed to identify the differentially expressed genes (DEGs) between the mutant and wild-type prawns. A total of 78,224 unigenes were obtained, and 1863 were identified as DEGs, in which 902 unigenes showed higher expression levels, while 961 unigenes presented lower expression levels in the mutant in comparison with the wild-type prawns. Based on Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes analysis, as well as further investigation of annotated DEGs, we found that the biological processes related to astaxanthin binding, transport, and metabolism presented significant differences between the mutant and the wild-type prawns. Some genes related to these processes, including crustacyanin, apolipoprotein D (ApoD), cathepsin, and cuticle proteins, were identified as DEGs between the two types of prawns. These data may provide important information for us to understand the molecular mechanism of the existence of a high level of free astaxanthin in the prawn.

Streblus asper Lour. exerts MAPK and SKN-1 mediated anti-aging, anti-photoaging activities and imparts neuroprotection by ameliorating Aβ in Caenorhabditis elegans

2021 ◽  
pp. 1-17
Author(s):  
Mani Iyer Prasanth ◽  
James Michael Brimson ◽  
Dicson Sheeja Malar ◽  
Anchalee Prasansuklab ◽  
Tewin Tencomnao
Keyword(s):  
Oxidative Stress ◽  
Caenorhabditis Elegans ◽  
Stress Resistance ◽  
Vital Role ◽  
Transgenic Strain ◽  
Wild Type ◽  
Neuroprotective Effects ◽  
C Elegans ◽  
Streblus Asper

BACKGROUND: Streblus asper Lour., has been reported to have anti-aging and neuroprotective efficacies in vitro. OBJECTIVE: To analyze the anti-aging, anti-photoaging and neuroprotective efficacies of S. asper in Caenorhabditis elegans. METHODS: C. elegans (wild type and gene specific mutants) were treated with S. asper extract and analyzed for lifespan and other health benefits through physiological assays, fluorescence microscopy, qPCR and Western blot. RESULTS: The plant extract was found to increase the lifespan, reduce the accumulation of lipofuscin and modulate the expression of candidate genes. It could extend the lifespan of both daf-16 and daf-2 mutants whereas the pmk-1 mutant showed no effect. The activation of skn-1 was observed in skn-1::GFP transgenic strain and in qPCR expression. Further, the extract can extend the lifespan of UV-A exposed nematodes along with reducing ROS levels. Additionally, the extract also extends lifespan and reduces paralysis in Aβ transgenic strain, apart from reducing Aβ expression. CONCLUSIONS: S. asper was able to extend the lifespan and healthspan of C. elegans which was independent of DAF-16 pathway but dependent on SKN-1 and MAPK which could play a vital role in eliciting the anti-aging, anti-photoaging and neuroprotective effects, as the extract could impart oxidative stress resistance and neuroprotection.

scholarly journals Escherichia coli MutM Suppresses Illegitimate Recombination Induced by Oxidative Stress

Genetics ◽  
1999 ◽  
Vol 151 (2) ◽  
pp. 439-446 ◽  
Author(s):  
Masaaki Onda ◽  
Katsuhiro Hanada ◽  
Hirokazu Kawachi ◽  
Hideo Ikeda
Keyword(s):  
Oxidative Stress ◽  
Escherichia Coli ◽  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Double Strand Breaks ◽  
Illegitimate Recombination ◽  
Recombination Analysis ◽  
Wild Type ◽  
Strand Breaks ◽  
In The Wild

Abstract DNA damage by oxidative stress is one of the causes of mutagenesis. However, whether or not DNA damage induces illegitimate recombination has not been determined. To study the effect of oxidative stress on illegitimate recombination, we examined the frequency of λbio transducing phage in the presence of hydrogen peroxide and found that this reagent enhances illegitimate recombination. To clarify the types of illegitimate recombination, we examined the effect of mutations in mutM and related genes on the process. The frequency of λbio transducing phage was 5- to 12-fold higher in the mutM mutant than in the wild type, while the frequency in the mutY and mutT mutants was comparable to that of the wild type. Because 7,8-dihydro-8-oxoguanine (8-oxoG) and formamido pyrimidine (Fapy) lesions can be removed from DNA by MutM protein, these lesions are thought to induce illegitimate recombination. Analysis of recombination junctions showed that the recombination at Hotspot I accounts for 22 or 4% of total λbio transducing phages in the wild type or in the mutM mutant, respectively. The preferential increase of recombination at nonhotspot sites with hydrogen peroxide in the mutM mutant was discussed on the basis of a new model, in which 8-oxoG and/or Fapy residues may introduce double-strand breaks into DNA.

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