Brain mitochondria from DJ-1 knockout mice show increased respiration-dependent hydrogen peroxide consumption

Abstract

Mutations in the DJ-1 gene have been shown to cause a rare autosomal-recessive genetic form of Parkinson’s disease (PD). The function of DJ-1 and its role in PD development has been linked to multiple pathways, however its exact role in the development of PD has remained elusive. It is thought that DJ-1 may play a role in regulating reactive oxygen species (ROS) formation and overall oxidative stress in cells through directly scavenging ROS itself, or through the regulation of ROS scavenging systems such as glutathione (GSH) or thioredoxin (Trx) or ROS producing complexes such as complex I of the electron transport chain. Previous work in this laboratory has demonstrated that isolated brain mitochondria consume H2O2 predominantly by the Trx/Thioredoxin Reductase (TrxR)/Peroxiredoxin (Prx) system in a respiration dependent manner (Drechsel et al., Journal of Biological Chemistry, 2010). Therefore we wanted to determine if mitochondrial H2O2 consumption was altered in brains from DJ-1 deficient mice (DJ-1-/-). Surprisingly, DJ-1-/- mice showed an increase in mitochondrial respiration-dependent H2O2 consumption compared to controls. To determine the basis of the increased H2O2 consumption in DJ1-/- mice, the activities of Trx, Thioredoxin Reductase (TrxR), GSH, glutathione disulfide (GSSG) and glutathione reductase (GR) were measured. Compared to control mice, brains from DJ-1-/- mice showed an increase in (1) mitochondrial Trx activity, (2) GSH and GSSG levels and (3) mitochondrial glutaredoxin (GRX) activity. Brains from DJ-1-/- mice showed a decrease in mitochondrial GR activity compared to controls. The increase in the enzymatic activities of mitochondrial Trx and total GSH levels may account for the increased H2O2 consumption observed in the brain mitochondria in DJ-1-/- mice perhaps as an adaptive response to chronic DJ-1 deficiency.

Mechanisms and roles of mitophagy in neurodegenerative diseases

“…DJ‐1 is localized to mitochondria as a constituent of the thioredoxin/apoptosis signal‐regulating kinase 1 (Trx/Ask1) complex, which can modulate the elimination of endogenous ROS . DJ‐1 deficiency will result in H 2 O 2 accumulation in brain mitochondria, elevated oxidative stress level, and death of DA neurons …”

Agmatine prevents acute chlorpromazine-induced neurotoxicity in rats

“…Očigledno je da AGM pokazuje protektivne efekte u odnosu na ćelijsku membranu samo u prisustvu oksidativnog stresa, u ovom slučaju izazvanog HPZ. To bi ukazivalo da se aktivacija procesa peroksidacije kod primene AGM ne odvija preko NO, već preko drugog mogućeg puta, a to je formiranje OH Uloga glutationa u zaštiti ćelija od toksičnih dejstava SR i drugih komponenata sa elektrofilnim svojstvima ogleda se u njegovom antioksidativnom dejstvu, jer neutrališe RVK unutar ćelije direktno ili preko ciklusa GPx/glutation (50,51). Povećanje nivoa ukupnog glutationa u kori prednjeg mozga 24 h posle trovanja HPZ je, uzevši u obzir njegovo antioksidativno dejstvo, rezultat aktivacije protektivnih mehanizama moždanog tkiva u ovim uslovima (Slika 3A).…”

DJ‐1 modulates mitochondrial response to oxidative stress: clues from a novel diagnosis of PARK7

“…The complex I defect could be the reason of the increased ROS production detected in patient fibroblasts at the basal conditions; in addition these cells showed, similar to what has been reported in the knockdown or knockout DJ‐1 cell models , a higher sensitivity to oxidative stress, displaying under stress conditions a dramatic increase in ROS production compared to control cell lines. Moreover, the increased oxidative stress was underlined by the high concentrations of GSSG and the altered GR activity in patient blood, resembling what has been found in brain mitochondria of DJ‐1 −/− knockout mice . It has been shown that DJ‐1 upregulates GSH synthesis to reduce ROS level during oxidative stress stimulating the expression of both SOD and glutamate cysteine ligase genes by an unknown mechanism .…”