DJ-1 regulation of mitochondrial function and autophagy through oxidative stress

McCoy, Melissa K.; Cookson, Mark

doi:10.4161/auto.7.5.14684

Cited by 139 publications

(102 citation statements)

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“…In addition, DJ-1 can be recruited to mitochondria following oxidative stress and contribute to protection against mitochondrial toxins. However, the loss of DJ-1 leads to alterations in mitochondrial phenotypes, including reduced mtΔψ, increased fragmentation and the accumulation of autophagic markers [14] . Our data demonstrated that RAB induced oxidative stress and dramatic mitochondrial swelling with a decrease in DJ-1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…RAB stimulates mitophagy in PCa cells and inhibits the PI3K/ Akt/mTOR pathway Because mitochondrial depolarization and the loss of protection against oxidative stress were able to cause severe mitochondrial damage and fragmentation, which was followed by the anchoring of LC3BII autophagolysosomes to mitochondrial membranes (mitophagy) [1,14] , we examined whether RAB could induce mitophagy. First, we visualized the colocalization of mitochondria and autophagolysosomes by electron microscopy of RAB-treated PC3 cells and dramatic mitochondrial swelling at 12 h and 24 h ( Figure 3A).…”

Section: Pca Cellsmentioning

confidence: 99%

“…DJ-1 acts as a redox-sensitive chaperone and sensor for oxidative stress [7] , and it is known to protect cells against oxidative stress as an antioxidant because its cysteine residues [14,15] . To investigate the effect of RAB on DJ-1 expression, we analyzed the time-dependent expression changes in the DJ-1 protein level with RAB treatment.…”

Section: Pca Cellsmentioning

confidence: 99%

“…The oxidative stress-induced early translocalization of DJ-1 into mitochondria is closely associated with its cytoprotective activity; DJ-1 is mainly localized in the cytoplasm, but under oxidative stress, it is translocated into mitochondria [13] . It has been reported that DJ-1 maintains mitochondrial functions during oxidative stress [14,15] , and the loss of DJ-1 leads to alterations in mitochondrial phenotypes such as a reduction in membrane potential and an increase in fragmentation; damaged mitochondria then promote mitochondrial clearance via the mitophagy pathway [14] . These events are thought to be a protective mechanism against oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro

Liu

et al. 2013

Acta Pharmacol Sin

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Aim: Retigeric acid B (RAB), a pentacyclic triterpenic acid from Lobaria kurokawae Yoshim, has been found to induce apoptosis in prostate cancer cells. The aim of this study was to investigate the roles of mitochondrial damage-caused mitophagy in RAB-induced prostate cancer cell death in vitro. Methods: Human prostate cancer PC3 and LNCaP cells were tested. Cell viability was analyzed with MTT assay. Cell apoptosis, ROS level and mitochondrial transmembrane potential (mtΔψ) were measured with flow cytometry. Autophagy-and apoptosis-related proteins were studied using Western blotting. GFP-LC3B puncta, mitochondrial swelling and mitophagy were examined morphologically. Quantitative RT-PCR was used to measure LC3B mRNA level, and siRNA was used to knock down LC3BII. Results: In both PC3 and LNCaP cells, RAB (15 µmol/L) increased ROS accumulation and decreased mtΔψ in a time-dependent manner. Furthermore, RAB induced mitochondrial swelling and mitophagy, significantly increased LC3B expression and conversion of LC3BI to LC3BII, and the elimination of mitochondria by LC3BII-containing autophagolysosomes. In addition, RAB suppressed the PI3K/Akt/mTOR pathway activation. Pretreatment of PC3 cells with autophagy inhibitor 3-MA (5 mmol/L) or the lysosomal protease inhibitor CQ (10 µmol/L) significantly increased RAB-induced apoptosis. Similar results were obtained in RAB-treated PC3 cells with LC3B knocked down. Conclusion: RAB induces mitochondrial damage and mitophagy that attenuates RAB-induced prostate cancer cell death. Thus, suppression of mitophagy might be a potential strategy for improving the chemotherapeutic effects of RAB.

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Section: Discussionmentioning

confidence: 99%

Section: Pca Cellsmentioning

confidence: 99%

Section: Pca Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro

Liu

et al. 2013

Acta Pharmacol Sin

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“…On the other hand, recent studies have reported that DJ-1 inhibits several apoptotic pathways such as pyrimidine tract-binding protein-associated splicing factor (PSF) / 54-kDa nuclear RNAbinding protein (p54nrb) pathway (25) and/or apoptosis signal regulating kinase 1 (ASK1) / homeodomain-interacting protein kinase (HIPK1) / death-domain-associated protein (Daxx) pathway (25,50). Moreover, DJ-1 may act to maintain mitochondrial function during oxidative stress, and thereby alter mitochondrial dynamics and autophagy indirectly (51,52). Based on these observations, we consider that the UCP0054278 / DJ-1 complex may maintain and enhance DJ-1-induced anti-oxidative and anti-apoptotic activation, and these responses may synergistically act to prevent both ROS production and neural cell death.…”

Section: Discussionmentioning

confidence: 99%

Protection Against Dopaminergic Neurodegeneration in Parkinson’s Disease–Model Animals by a Modulator of the Oxidized Form of DJ-1, a Wild-type of Familial Parkinson’s Disease–Linked PARK7

et al. 2011

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Abstract. DJ-1, Parkinson's disease PARK7, acts as an oxidative stress sensor in neural cells. Recently, we identified the DJ-1 modulator UCP0054278 by in silico virtual screening. However, the effect of the peripheral administration of UCP0054278 on an in vivo Parkinson's disease (PD) model is unclear. Therefore, in the present study, we examined the effects of the peripheral administration of UCP0054278 on both 6-OHDA-microinjected rats and rotenone-treated mice as acute and chronic animal models of PD, respectively. The peripheral administration of UCP0054278 prevented 6-OHDA-and rotenone-induced dopaminergic neural cell death and restored the defect in locomotion in these models of PD. In addition, 6-OHDA-or rotenone-induced neural cell death and the production of reactive oxygen species were significantly inhibited by UCP0054278 in normal SH-SY5Y cells, but not in DJ-1-knockdown cells. These results suggest that UCP0054278 interacts with endogenous DJ-1 and then produces antioxidant and neuroprotective responses in both in vivo and in vitro models of PD. The present study raises the possibility that DJ-1 stimulatory modulators, such as UCP0054278, may be a new type of dopaminergic neuroprotective drug for the treatment of PD.

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Mitochondrial accumulation under oxidative stress is due to defects in autophagy

Luo

Wang

et al. 2012

J of Cellular Biochemistry

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Mitochondrial dynamics maintains normal mitochondrial function by degrading damaged mitochondria and generating newborn mitochondria. The accumulation of damaged mitochondria influences the intracellular environment by promoting mitochondrial dysfunction, and thus initiating a vicious cycle. Oxidative stress induces mitochondrial malfunction, which is involved in many cardiovascular diseases. However, the mechanism of mitochondrial accumulation in cardiac myoblasts remains unclear. We observed mitochondrial dysfunction and an increase in mitochondrial mass under the oxidative conditions produced by tert-butyl hydroperoxide (tBHP) in cardiac myoblast H9c2 cells. However, in contrast to the increase in mitochondrial mass, mitochondrial DNA (mtDNA) decreased, suggesting that enhanced mitochondrial biogenesis may be not the primary cause of the mitochondrial accumulation. Therefore, we investigated changes in a number of proteins involved in autophagy. Beclin1, Atg12-Atg5 conjugate, Atg7 contents decreased but LC3-II accumulated in tBHP-treated H9c2 cells. Moreover, the capacity for acid hydrolysis decreased in H9c2 cells. We also demonstrated a decrease in DJ-1 protein under the oxidative conditions that deregulate mitochondrial dynamics. These results reveal that autophagy became defective under oxidative stress. We therefore suggest that defects in autophagy mediate mitochondrial accumulation under these conditions.

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DJ-1 regulation of mitochondrial function and autophagy through oxidative stress

Cited by 139 publications

References 1 publication

Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro

Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro

Protection Against Dopaminergic Neurodegeneration in Parkinson’s Disease–Model Animals by a Modulator of the Oxidized Form of DJ-1, a Wild-type of Familial Parkinson’s Disease–Linked PARK7

Mitochondrial accumulation under oxidative stress is due to defects in autophagy

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