Nuclear magnetic resonance studies of 6-hydroxydopamine and its interactions with mercapto-containing model compounds. Evaluation of possible mechanism for neurocytotoxicity

Granot, Joseph; Rotman, Avner

doi:10.1021/bi00605a018

Cited by 5 publications

(3 citation statements)

References 16 publications

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“…Finally, paraquat also impairs NADPH dependent antioxidant systems such as the peroxiredoxins/thioredoxin/thioredoxin reductase ( data not shown ). 6-OHDA-induced oxidative damage has been linked to depletion/adduction of intracellular thiols (GSH and cysteine) and generation of both extracellular and intracellular ROS. ,, Thus, there is no single antioxidant or antioxidant system that would be expected to efficiently prevent ROS formation and oxidative stress induced by any of these toxins and addressing this issue requires extensive and additional investigation.…”

Section: Results and Discusionmentioning

confidence: 99%

Alterations in Energy/Redox Metabolism Induced by Mitochondrial and Environmental Toxins: A Specific Role for Glucose-6-Phosphate-Dehydrogenase and the Pentose Phosphate Pathway in Paraquat Toxicity

Lei¹,

Zavala-Flores²,

García-García³

et al. 2014

ACS Chem. Biol.

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Parkinson’s disease (PD) is a multifactorial disorder with a complex etiology including genetic risk factors, environmental exposures, and aging. While energy failure and oxidative stress have largely been associated with the loss of dopaminergic cells in PD and the toxicity induced by mitochondrial/environmental toxins, very little is known regarding the alterations in energy metabolism associated with mitochondrial dysfunction and their causative role in cell death progression. In this study, we investigated the alterations in the energy/redox-metabolome in dopaminergic cells exposed to environmental/mitochondrial toxins (paraquat, rotenone, 1-methyl-4-phenylpyridinium [MPP+], and 6-hydroxydopamine [6-OHDA]) in order to identify common and/or different mechanisms of toxicity. A combined metabolomics approach using nuclear magnetic resonance (NMR) and direct-infusion electrospray ionization mass spectrometry (DI-ESI-MS) was used to identify unique metabolic profile changes in response to these neurotoxins. Paraquat exposure induced the most profound alterations in the pentose phosphate pathway (PPP) metabolome. 13C-glucose flux analysis corroborated that PPP metabolites such as glucose-6-phosphate, fructose-6-phosphate, glucono-1,5-lactone, and erythrose-4-phosphate were increased by paraquat treatment, which was paralleled by inhibition of glycolysis and the TCA cycle. Proteomic analysis also found an increase in the expression of glucose-6-phosphate dehydrogenase (G6PD), which supplies reducing equivalents by regenerating nicotinamide adenine dinucleotide phosphate (NADPH) levels. Overexpression of G6PD selectively increased paraquat toxicity, while its inhibition with 6-aminonicotinamide inhibited paraquat-induced oxidative stress and cell death. These results suggest that paraquat “hijacks” the PPP to increase NADPH reducing equivalents and stimulate paraquat redox cycling, oxidative stress, and cell death. Our study clearly demonstrates that alterations in energy metabolism, which are specific for distinct mitochondiral/environmental toxins, are not bystanders to energy failure but also contribute significant to cell death progression.

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Section: Results and Discusionmentioning

confidence: 99%

Alterations in Energy/Redox Metabolism Induced by Mitochondrial and Environmental Toxins: A Specific Role for Glucose-6-Phosphate-Dehydrogenase and the Pentose Phosphate Pathway in Paraquat Toxicity

Lei¹,

Zavala-Flores²,

García-García³

et al. 2014

ACS Chem. Biol.

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“…In chromaffin vesicles ( Fig. 2A), (nor)adrenalin is bound, together with ATP, Ca 2+ and chromogranin in a ternary storage complex [7,42], in which Ca 2+ serves as a stabiliserin contrast to trichocyst contents where Ca 2+ causes physiological destabilisation for cargo extrusion [13,26]. In conclusion, contents are widely different in the proto-and metazoan dense core vesicle systems analysed so far.…”

Section: Biogenesis and Transport Of Secretory Organellesmentioning

confidence: 89%

The remembrance of the things past: Conserved signalling pathways link protozoa to mammalian nervous system

Plattner

Verkhratsky

2018

Cell Calcium

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The aim of the present article is to analyse the evolutionary links between protozoa and neuronal and neurosecretory cells. To this effect we employ functional and topological data available for ciliates, in particular for Paramecium. Of note, much less data are available for choanoflagellates, the progenitors of metazoans, which currently are in the focus of metazoan genomic data mining. Key molecular players are found from the base to the highest levels of eukaryote evolution, including neurones and neurosecretory cells. Several common fundamental mechanisms, such as SNARE proteins and assembly of exocytosis sites, GTPases, Ca-sensors, voltage-gated Ca-influx channels and their inhibition by the forming Ca/calmodulin complex are conserved, albeit with different subcellular channel localisation, from protozoans to man. Similarly, Ca-release channels represented by InsP receptors and putative precursors of ryanodine receptors, which all emerged in protozoa, serve for focal intracellular Ca signalling from ciliates to mammalian neuronal cells, eventually in conjunction with store-operated Ca-influx. Restriction of Ca signals by high capacity/low affinity Ca-binding proteins is maintained throughout the evolutionary tree although the proteins involved differ between the taxa. Phosphatase 2B/calcineurin appears to be involved in signalling and in membrane recycling throughout evolution. Most impressive example of evolutionary conservation is the sub-second dynamics of exocytosis-endocytosis coupling in Paramecium cells, with similar kinetics in neuronal and neurosecretory systems. Numerous cell surface receptors and channels that emerge in protozoa operate in the human nervous system, whereas a variety of cell adhesion molecules are newly "invented" during evolution, enabled by an increase in gene numbers, alternative splice forms and transcription factors. Thereby, important regulatory and signalling molecules are retained as a protozoan heritage.

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“…Calcium has been deliberately ignored even though its role in the folding of granins. Data adapted from (Granot and Rotman 1978).…”

Section: The Interaction Of Vesicular Components In Vivo Approachesmentioning

confidence: 99%

The intravesicular cocktail and its role in the regulation of exocytosis

Estévez-Herrera

González-Santana

Baz‐Dávila

et al. 2016

Journal of Neurochemistry

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The accumulation of neurotransmitters within secretory vesicles (SVs) far exceeds the theoretical tonic concentrations in the cytosol, a phenomenon that has captivated the attention of scientists for decades. For instance, chromaffin granules can accumulate close to molar concentrations of catecholamines, along with many other products like ATP, calcium, peptides, chromogranins, ascorbate, and other nucleotides. In this short review, we will summarize the interactions that are currently believed to occur between the elements that make up the vesicular cocktail in the acidic environment of SVs, and how they permit the accumulation of such high concentrations of certain components. In addition, we will examine how the vesicular cocktail regulates the exocytosis of neurotransmitters.

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Nuclear magnetic resonance studies of 6-hydroxydopamine and its interactions with mercapto-containing model compounds. Evaluation of possible mechanism for neurocytotoxicity

Cited by 5 publications

References 16 publications

Alterations in Energy/Redox Metabolism Induced by Mitochondrial and Environmental Toxins: A Specific Role for Glucose-6-Phosphate-Dehydrogenase and the Pentose Phosphate Pathway in Paraquat Toxicity

Alterations in Energy/Redox Metabolism Induced by Mitochondrial and Environmental Toxins: A Specific Role for Glucose-6-Phosphate-Dehydrogenase and the Pentose Phosphate Pathway in Paraquat Toxicity

The remembrance of the things past: Conserved signalling pathways link protozoa to mammalian nervous system

The intravesicular cocktail and its role in the regulation of exocytosis

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