Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-soluble Coenzyme Q10

McCarthy, Susan A.; Somayajulu, Mallika; Sikorska, Marianna; Borowy-Borowski, Henryk; Pandey, Siyaram

doi:10.1016/j.taap.2004.04.019

Cited by 213 publications

(154 citation statements)

References 30 publications

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“…Mitochondrial dysfunction and mitochondrial-induced apoptosis have been demonstrated in paraquat toxicity in dopaminergic cells (Gomez et al, 2007;GonzalezPolo et al, 2004;McCarthy et al, 2004;Richardson et al, 2005). Our results show that paraquat-induced cytotoxicity is preceded by the increase in ROS production.…”

Section: Discussionsupporting

confidence: 61%

“…Increases in ROS production by oxidases in the mitochondrial respiratory chain have been regarded as an important process for toxin-induced apoptosis (Gonzalez-Polo et al, 2004;McCarthy et al, 2004). Mitochondrial dysfunction and mitochondrial-induced apoptosis have been demonstrated in paraquat toxicity in dopaminergic cells (Gomez et al, 2007;GonzalezPolo et al, 2004;McCarthy et al, 2004;Richardson et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Miller

Sun

2007

Brain Research

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Excess production of reactive oxygen species (ROS) is an important mechanism underlying the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease (PD) which is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Exposure to paraquat, an herbicide with structure similar to the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium (MPP + ), has been shown to produce PD-like symptoms. Despite previous focus on the dopaminergic neurons and signaling pathways involved in their cell death, recent studies have implicated microglial cells as a major producer of ROS for damaging neighboring neurons. In this study, we examined the source of ROS and the underlying signaling pathway for paraquat-induced cytotoxicity to BV-2 microglial cells. Paraquat-induced ROS production (including superoxide anions) in BV-2 cells was accompanied by translocation of the p67phox cytosolic subunit of NADPH oxidase to the membrane. Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol. Apocynin and DPI also rescued cells from paraquat-induced toxicity. The inhibitors for protein kinase C delta (PKCδ) or extracellular signal-regulated kinases (ERK1/2) could partially attenuate paraquat-induced ROS production and cell death. Rottlerin, a selective PKCδ inhibitor, also inhibited paraquat-induced translocation of p67phox. Taken together, this study demonstrates the involvement of ROS from NADPH oxidase in mediating paraquat cytotoxicity in BV-2 microglial cells and this process is mediated through PKCδ-and ERK-dependent pathways.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Miller

Sun

2007

Brain Research

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“…To test whether dYME1L del flies were also more sensitive, compared with wild type, to oxidative stress, we treated them with paraquat, a known inducer of oxidative damages. 47 Paraquat treatment led to premature mortality in both wild-type flies and dYME1L del flies, but dYME1L del flies were much more sensitive to paraquat compared with wildtype flies (Figure 6f): it took only 3 days after paraquat treatment for half of the mutant flies to die. More than 50% of i-AAA mutation causes apoptotic degeneration Y Qi et al the wild-type flies still survived 10 days after paraquat administration, but almost all of the dYME1L del flies had died by that time.…”

Section: Resultsmentioning

confidence: 99%

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Liu

Daniels

et al. 2015

Cell Death Differ

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Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L del ). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1L del flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1L del flies had reduced complex I (NADH/ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency.

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“…However, a strict control over the intracellular concentration range is required to achieve optimal mitochondrial protection and retention of physiological functions. 13,58 Exposure of microglia cells to antimycin A (A.A, 1 μM, 24 h) led to a significant reduction in mitochondrial potential as measured by TMRE fluorescence (200 nM, 30 min). CoQ10 treatment alone and CoQ10 from the targeted micelle corrected this mitochondrial impairment, whereas CoQ10 in nontargeted micelles was ineffective.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Design and Evaluation of Multifunctional Nanocarriers for Selective Delivery of Coenzyme Q10 to Mitochondria

et al. 2011

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Impairments of mitochondrial functions have been associated with failure of cellular functions in different tissues, leading to various pathologies. We report here a mitochondria-targeted nanodelivery system for coenzyme Q10 (CoQ10) that can reach mitochondria and deliver CoQ10 in adequate quantities. Multifunctional nanocarriers based on ABC miktoarm polymers (A = poly(ethylene glycol (PEG), B = polycaprolactone (PCL), and C = triphenylphosphonium bromide (TPPBr)) were synthesized using a combination of click chemistry with ring-opening polymerization, self-assembled into nanosized micelles, and were employed for CoQ10 loading. Drug loading capacity (60 wt %), micelle size (25−60 nm), and stability were determined using a variety of techniques. The micelles had a small critical association concentration and were colloidally stable in solution for more than 3 months. The extraordinarily high CoQ10 loading capacity in the micelles is attributed to good compatibility between CoQ10 and PCL, as indicated by the low Flory−Huggins interaction parameter. Confocal microscopy studies of the fluorescently labeled polymer analog together with the mitochondria-specific vital dye label indicated that the carrier did indeed reach mitochondria. The high CoQ10 loading efficiency allowed testing of micelles within a broad concentration range and provided evidence for CoQ10 effectiveness in two different experimental paradigms: oxidative stress and inflammation. Combined results from chemical, analytical, and biological experiments suggest that the new miktoarm-based carrier provides a suitable means of CoQ10 delivery to mitochondria without loss of drug effectiveness. The versatility of the click chemistry used to prepare this new mitochondria-targeting nanocarrier offers a widely applicable, simple, and easily reproducible procedure to deliver drugs to mitochondria or other intracellular organelles.

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Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-soluble Coenzyme Q10

Cited by 213 publications

References 30 publications

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

Design and Evaluation of Multifunctional Nanocarriers for Selective Delivery of Coenzyme Q10 to Mitochondria

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