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

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.

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

eLife ◽

10.7554/elife.48828 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 9

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.

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Neuronal Cells Rearrangement During Aging and Neurodegenerative Disease: Metabolism, Oxidative Stress and Organelles Dynamic

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2019.00132 ◽

2019 ◽

Vol 12 ◽

Cited By ~ 27

Author(s):

Vanessa Castelli ◽

Elisabetta Benedetti ◽

Andrea Antonosante ◽

Mariano Catanesi ◽

Giuseppina Pitari ◽

...

Keyword(s):

Oxidative Stress ◽

Neurodegenerative Disease ◽

Neuronal Cells

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In vitro assessment of the cytotoxic, genotoxic and oxidative stress effects of the synthetic cannabinoid JWH-018 in human SH-SY5Y neuronal cells

Toxicology Research ◽

10.1093/toxres/tfaa078 ◽

2020 ◽

Vol 9 (6) ◽

pp. 734-740

Author(s):

Yigit Sezer ◽

Ayse Tarbin Jannuzzi ◽

Marilyn A Huestis ◽

Buket Alpertunga

Keyword(s):

Oxidative Stress ◽

Neuronal Cells ◽

Underlying Mechanism ◽

Synthetic Cannabinoid ◽

Stress Effects ◽

Legal High ◽

New Generation ◽

And Oxidative Stress

Abstract Background: JWH-018 was the first synthetic cannabinoid introduced as a legal high and the first of the new generation of novel psychoactive substances that flooded worldwide drug markets. JWH-018 was marketed as “spice,” “herbal incense,” or “herbal blend,” as a popular and legal (at the time) alternative to cannabis (marijuana). JWH-018 is a potent synthetic cannabinoid with considerable toxicity associated with its use. JWH-018 has qualitatively similar but quantitatively greater pharmacological effects than cannabis, leading to intoxications and even deaths. The mechanisms of action of the drug’s toxicity require research, and thus, the aim of the present study was to investigate the toxicological profile of JWH-018 in human SH-SY5Y neuronal cells. Methods: SH-SY5Y neuronal cells were exposed to increasing concentrations from 5 to 150 μM JWH-018 over 24 h. Cytotoxicity, DNA damage, the apoptotic/necrotic rate, and oxidative stress were assessed following SH-SY5Y exposure. Results: JWH-018 did not produce a significant decrease in SH-SY5Y cell viability, did not alter apoptotic/necrotic rate, and did not cause genotoxicity in SH-SY5Y cells with 24-h exposure. Glutathione reductase and catalase activities were significantly reduced; however, there was no significant change in glutathione peroxidase activity. Also, JWH-018 treatment significantly decreased glutathione concentrations, significantly increased protein carbonylation, and significantly increased malondialdehyde (MDA) concentrations. For significance, all P < 0.05. Discussion/Conclusion: JWH-018 produced oxidative stress in SH-SY5Y cells that could be an underlying mechanism of JWH-018 neurotoxicity. Additional in vivo animal and human-based studies are needed to confirm our findings.

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

10.1101/438101 ◽

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.

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

Translational Psychiatry ◽

10.1038/s41398-021-01392-w ◽

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.

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Pirlindole and dehydropirlindole protect rat cultured neuronal cells against oxidative stress-induced cell death through a mechanism unrelated to MAO-A inhibition

British Journal of Pharmacology ◽

10.1038/sj.bjp.0704519 ◽

2002 ◽

Vol 135 (3) ◽

pp. 713-720 ◽

Cited By ~ 9

Author(s):

A Boland ◽

J Gérardy ◽

D Mossay ◽

D Delapierre ◽

V Seutin

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Neuronal Cells ◽

Mao A

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MiR-22-3p Suppresses Vascular Remodeling and Oxidative Stress by Targeting CHD9 during the Development of Hypertension

Journal of Vascular Research ◽

10.1159/000514311 ◽

2021 ◽

pp. 1-11

Author(s):

Hanqing Chen ◽

Xiru Xu ◽

Zhengqing Liu ◽

Yong Wu

Keyword(s):

Oxidative Stress ◽

Vascular Remodeling ◽

Underlying Mechanism ◽

Inhibitory Effect ◽

Spontaneously Hypertensive ◽

Aortic Smooth Muscle ◽

Phenotype Switch ◽

And Oxidative Stress

Hypertension is considered a risk factor for a series of systematic diseases. Known factors including genetic predisposition, age, and diet habits are strongly associated with the initiation of hypertension. The current study aimed to investigate the role of miR-22-3p in hypertension. In this study, we discovered that the miR-22-3p level was significantly decreased in the thoracic aortic vascular tissues and aortic smooth muscle cells (ASMCs) of spontaneously hypertensive rats. Functionally, the overexpression of miR-22-3p facilitated the switch of ASMCs from the synthetic to contractile phenotype. To investigate the underlying mechanism, we predicted 11 potential target mRNAs for miR-22-3p. After screening, chromodomain helicase DNA-binding 9 (CHD9) was validated to bind with miR-22-3p. Rescue assays showed that the co-overexpression of miR-22-3p and CHD9 reversed the inhibitory effect of miR-22-3p mimics on cell proliferation, migration, and oxidative stress in ASMCs. Finally, miR-22-3p suppressed vascular remodeling and oxidative stress in vivo. Overall, miR-22-3p regulated ASMC phenotype switch by targeting CHD9. This new discovery provides a potential insight into hypertension treatment.

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