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Thioredoxin Reductase Deficiency Potentiates Oxidative Stress, Mitochondrial Dysfunction and Cell Death in Dopaminergic Cells

Mitochondria are considered major generators of cellular reactive oxygen species (ROS) which are implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD). We have recently shown that isolated mitochondria consume hydrogen peroxide (H(2)O(2)) in a substrate- and r...

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Autores principales: Lopert, Pamela, Day, Brian J., Patel, Manisha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511321/
https://www.ncbi.nlm.nih.gov/pubmed/23226354
http://dx.doi.org/10.1371/journal.pone.0050683
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author Lopert, Pamela
Day, Brian J.
Patel, Manisha
author_facet Lopert, Pamela
Day, Brian J.
Patel, Manisha
author_sort Lopert, Pamela
collection PubMed
description Mitochondria are considered major generators of cellular reactive oxygen species (ROS) which are implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD). We have recently shown that isolated mitochondria consume hydrogen peroxide (H(2)O(2)) in a substrate- and respiration-dependent manner predominantly via the thioredoxin/peroxiredoxin (Trx/Prx) system. The goal of this study was to determine the role of Trx/Prx system in dopaminergic cell death. We asked if pharmacological and lentiviral inhibition of the Trx/Prx system sensitized dopaminergic cells to mitochondrial dysfunction, increased steady-state H(2)O(2) levels and death in response to toxicants implicated in PD. Incubation of N27 dopaminergic cells or primary rat mesencephalic cultures with the Trx reductase (TrxR) inhibitor auranofin in the presence of sub-toxic concentrations of parkinsonian toxicants paraquat; PQ or 6-hydroxydopamine; 6OHDA (for N27 cells) resulted in a synergistic increase in H(2)O(2) levels and subsequent cell death. shRNA targeting the mitochondrial thioredoxin reductase (TrxR2) in N27 cells confirmed the effects of pharmacological inhibition. A synergistic decrease in maximal and reserve respiratory capacity was observed in auranofin treated cells and TrxR2 deficient cells following incubation with PQ or 6OHDA. Additionally, TrxR2 deficient cells showed decreased basal mitochondrial oxygen consumption rates. These data demonstrate that inhibition of the mitochondrial Trx/Prx system sensitizes dopaminergic cells to mitochondrial dysfunction, increased steady-state H(2)O(2), and cell death. Therefore, in addition to their role in the production of cellular H(2)O(2) the mitochondrial Trx/Prx system serve as a major sink for cellular H(2)O(2) and its disruption may contribute to dopaminergic pathology associated with PD.
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spelling pubmed-35113212012-12-05 Thioredoxin Reductase Deficiency Potentiates Oxidative Stress, Mitochondrial Dysfunction and Cell Death in Dopaminergic Cells Lopert, Pamela Day, Brian J. Patel, Manisha PLoS One Research Article Mitochondria are considered major generators of cellular reactive oxygen species (ROS) which are implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD). We have recently shown that isolated mitochondria consume hydrogen peroxide (H(2)O(2)) in a substrate- and respiration-dependent manner predominantly via the thioredoxin/peroxiredoxin (Trx/Prx) system. The goal of this study was to determine the role of Trx/Prx system in dopaminergic cell death. We asked if pharmacological and lentiviral inhibition of the Trx/Prx system sensitized dopaminergic cells to mitochondrial dysfunction, increased steady-state H(2)O(2) levels and death in response to toxicants implicated in PD. Incubation of N27 dopaminergic cells or primary rat mesencephalic cultures with the Trx reductase (TrxR) inhibitor auranofin in the presence of sub-toxic concentrations of parkinsonian toxicants paraquat; PQ or 6-hydroxydopamine; 6OHDA (for N27 cells) resulted in a synergistic increase in H(2)O(2) levels and subsequent cell death. shRNA targeting the mitochondrial thioredoxin reductase (TrxR2) in N27 cells confirmed the effects of pharmacological inhibition. A synergistic decrease in maximal and reserve respiratory capacity was observed in auranofin treated cells and TrxR2 deficient cells following incubation with PQ or 6OHDA. Additionally, TrxR2 deficient cells showed decreased basal mitochondrial oxygen consumption rates. These data demonstrate that inhibition of the mitochondrial Trx/Prx system sensitizes dopaminergic cells to mitochondrial dysfunction, increased steady-state H(2)O(2), and cell death. Therefore, in addition to their role in the production of cellular H(2)O(2) the mitochondrial Trx/Prx system serve as a major sink for cellular H(2)O(2) and its disruption may contribute to dopaminergic pathology associated with PD. Public Library of Science 2012-11-30 /pmc/articles/PMC3511321/ /pubmed/23226354 http://dx.doi.org/10.1371/journal.pone.0050683 Text en © 2012 Lopert et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lopert, Pamela
Day, Brian J.
Patel, Manisha
Thioredoxin Reductase Deficiency Potentiates Oxidative Stress, Mitochondrial Dysfunction and Cell Death in Dopaminergic Cells
title Thioredoxin Reductase Deficiency Potentiates Oxidative Stress, Mitochondrial Dysfunction and Cell Death in Dopaminergic Cells
title_full Thioredoxin Reductase Deficiency Potentiates Oxidative Stress, Mitochondrial Dysfunction and Cell Death in Dopaminergic Cells
title_fullStr Thioredoxin Reductase Deficiency Potentiates Oxidative Stress, Mitochondrial Dysfunction and Cell Death in Dopaminergic Cells
title_full_unstemmed Thioredoxin Reductase Deficiency Potentiates Oxidative Stress, Mitochondrial Dysfunction and Cell Death in Dopaminergic Cells
title_short Thioredoxin Reductase Deficiency Potentiates Oxidative Stress, Mitochondrial Dysfunction and Cell Death in Dopaminergic Cells
title_sort thioredoxin reductase deficiency potentiates oxidative stress, mitochondrial dysfunction and cell death in dopaminergic cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511321/
https://www.ncbi.nlm.nih.gov/pubmed/23226354
http://dx.doi.org/10.1371/journal.pone.0050683
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