Dec 12, 2012

Thioredoxin reductase deficiency potentiates oxidative stress, mitochondrial dysfunction and cell death in dopaminergic cells

PloS One
Pamela LopertManisha Patel

Abstract

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 (H₂O₂) 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 H₂O₂ 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 H₂O₂ 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...Continue Reading

  • References43
  • Citations37

References

Mentioned in this Paper

Neuro-Oncological Ventral Antigen 2
Real-Time Polymerase Chain Reaction
Manganese Superoxide Dismutase
Mechanism of Cell Death
Pathogenic Aspects
Biochemical Pathway
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Paragreen A
Subfamily lentivirinae
Cytochrome C Oxidase

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