Drp1-mediated mitochondrial fission contributes to mitophagy in paraquat-induced neuronal cell damage

Chen, Nengzhou; Guo, Zhenkun; Luo, Zhousong; Zheng, Fuli; Shao, Wenya; Yu, Guangxia; Cai, Ping; Wu, Siying

doi:10.1016/j.envpol.2020.116413

Cited by 29 publications

(18 citation statements)

References 63 publications

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“…Acute, low levels of PQ have been reported to adversely affect mitochondrial dynamics including excessive levels of ssion and mitophagy with loss of TOM20 and other mitochondrial markers such as cytochrome oxidase IV in cultured neuronal cells [35]. The translocase of the outer mitochondrial membrane (TOM, TOM20 is a major subunit of TOM) is responsible for the import of nuclear-encoded proteins into the mitochondria.…”

Section: Resultsmentioning

confidence: 99%

Small Molecule-Mediated Allosteric Activation of the Base Excision Repair Enzyme 8-Oxoguanine DNA Glycosylase: Impact on Mitochondrial Function

Tian¹,

Katchur²,

Jiang³

et al. 2022

Preprint

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8-Oxoguanine DNA glycosylase (OGG1) initiates base excision repair of the oxidative DNA damage product 8-oxoguanine. OGG1 is bifunctional; catalyzing glycosyl bond cleavage, followed by phosphodiester backbone incision via a β-elimination apurinic lyase reaction. The product from the glycosylase reaction, 8-oxoguanine, and its analogues, 8-bromoguanine and 8-aminoguanine, trigger the rate-limiting AP lyase reaction. The precise activation mechanism remains unclear. The product-assisted catalysis hypothesis suggests that 8-oxoguanine and analogues bind at the product recognition (PR) pocket to enhance strand cleavage as catalytic bases. Alternatively, they may allosterically activate OGG1 by binding outside of the PR pocket to induce an active-site conformational change to accelerate apurinic lyase. Herein, steady-state kinetic analyses demonstrated random binding of substrate and activator. 9-Deazaguanine, which can’t function as a substrate-competent base, activated OGG1, albeit with a lower Emax value than 8-bromoguanine and 8-aminoguanine. Random compound screening identified small molecules with Emax values similar to 8-bromoGua. Paraquat-induced mitochondrial dysfunction was attenuated by several small molecule OGG1 activators; benefits included enhanced mitochondrial membrane and DNA integrity, less cytochrome c translocation, ATP preservation, and mitochondrial membrane dynamics. Our results support an allosteric mechanism of OGG1 and not product-assisted catalysis. OGG1 small molecule activators may improve mitochondrial function in oxidative stress-related diseases.

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Section: Resultsmentioning

confidence: 99%

Small Molecule-Mediated Allosteric Activation of the Base Excision Repair Enzyme 8-Oxoguanine DNA Glycosylase: Impact on Mitochondrial Function

Tian¹,

Katchur²,

Jiang³

et al. 2022

Preprint

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“…Mitochondria are also transported across the cell body and synapses to ensure that energy requirements are met between different subcellular compartments. Excessive mitochondrial fission is widely thought to be the cause of mitophagy, leading to dopaminergic neurodegeneration in PD models ( Chen et al, 2021 ). It is believed that dysregulation of mitochondrial dynamics is linked with neuroinflammation through the induction of interleukin-10 (IL-10) and reduction of tumor necrosis factor-α (TNF-α) secretion ( de Oliveira et al, 2021 ).…”

Section: Mitochondrial Quality Control In Parkinson’s Diseasementioning

confidence: 99%

Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy

Gao

Yang²,

Gu³

et al. 2022

Front. Aging Neurosci.

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Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders worldwide. There are currently no cures or preventative treatments for PD. Emerging evidence indicates that mitochondrial dysfunction is closely associated with pathogenesis of sporadic and familial PD. Because dopaminergic neurons have high energy demand, cells affected by PD exhibit mitochondrial dysfunction that promotes the disease-defining the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The mitochondrion has a particularly important role as the cellular “powerhouse” of dopaminergic neurons. Therefore, mitochondria have become a promising therapeutic target for PD treatments. This review aims to describe mitochondrial dysfunction in the pathology of PD, outline the genes associated with familial PD and the factors related to sporadic PD, summarize current knowledge on mitochondrial quality control in PD, and give an overview of therapeutic strategies for targeting mitochondria in neuroprotective interventions in PD.

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“…Stressful conditions such as nutritional deficiency or exposure to toxins impairs mitochondria driven -MFN1, MFN2 and OPA1 mediate fusion process (Archer, 2013). Severe mitochondrial damage promotes DRP1 and FIS1 facilitates fission (X. and produces smaller fragments of mitochondria for clearance by mitophagy (Chen et al, 2021). Despite this data, it still remains unclear as to how the defective mitochondria decide between fusion and fission.…”

Section: Impaired Mitophagymentioning

confidence: 99%

“…Alterations in fission and fusion process (a crucial part of mitophagy) play an important role in neurodegenerative diseases like AD, PD, stroke etc. (Chen et al, 2021; Trombetta-Lima et al, 2021). The regulation of fission and fusion is governed by several key proteins including the dynamin-related protein 1 (DRP1), the mitochondrial fusion proteins 1, 2 (MFN1, MFN2) and the optic atrophy 1 (OPA1) protein (Yu-Wai-Man et al, 2014; Xi et al, 2018).…”

Section: Mitochondrial Dysfunction In Pdmentioning

confidence: 99%

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Mitochondrial and Organellar Crosstalk in Parkinson’s Disease

et al. 2021

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Mitochondrial dysfunction is a well-established pathological event in Parkinson’s disease (PD). Proteins misfolding and its impaired cellular clearance due to altered autophagy/mitophagy/pexophagy contribute to PD progression. It has been shown that mitochondria have contact sites with endoplasmic reticulum (ER), peroxisomes and lysosomes that are involved in regulating various physiological processes. In pathological conditions, the crosstalk at the contact sites initiates alterations in intracellular vesicular transport, calcium homeostasis and causes activation of proteases, protein misfolding and impairment of autophagy. Apart from the well-reported molecular changes like mitochondrial dysfunction, impaired autophagy/mitophagy and oxidative stress in PD, here we have summarized the recent scientific reports to provide the mechanistic insights on the altered communications between ER, peroxisomes, and lysosomes at mitochondrial contact sites. Furthermore, the manuscript elaborates on the contributions of mitochondrial contact sites and organelles dysfunction to the pathogenesis of PD and suggests potential therapeutic targets.

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Drp1-mediated mitochondrial fission contributes to mitophagy in paraquat-induced neuronal cell damage

Cited by 29 publications

References 63 publications

Small Molecule-Mediated Allosteric Activation of the Base Excision Repair Enzyme 8-Oxoguanine DNA Glycosylase: Impact on Mitochondrial Function

Small Molecule-Mediated Allosteric Activation of the Base Excision Repair Enzyme 8-Oxoguanine DNA Glycosylase: Impact on Mitochondrial Function

Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy

Mitochondrial and Organellar Crosstalk in Parkinson’s Disease

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