6-Hydroxydopamine induces mitochondrial ERK activation

Kulich, Scott; Horbinski, Craig; Patel, Manisha; Chu, Charleen T.

doi:10.1016/j.freeradbiomed.2007.04.028

Cited by 84 publications

(65 citation statements)

References 83 publications

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“…24 Early transient ERK1/2 activation accompanied by nuclear translocation is associated with enhanced neuronal survival, 21,22,54,55 while cytoplasmic ERK1/2 without evidence of nuclear localization is typical of degenerating neurons of Alzheimer's disease, 50 and in PD and related models. 25,35 While it is not possible to tell from human autopsy studies whether ERK1/2 regulates mitochondrial turnover or is passively localized to mitochondria and AVs, the current study indicates that activity level-dependent localization of ERK2 to mitochondria is sufficient to induce mitophagy. Moreover, dominant interfering ERK2-KD expression and the MEK inhibitor U0126 prevented both generation and colocalization of ERK2 granules with mitochondria, suppressing 6-OHDA induced mitophagy ( Fig.…”

Section: Discussionmentioning

confidence: 59%

“…The mechanism by which activated ERK2 is enriched in mitochondria is still unknown. While the involvement of mitochondrial reactive oxygen species in redox activation of ERK1/2 suggests a role for in situ phosphorylation, 35,56 the GFP-ERK2 data supports a mechanism involving mitochondrial translocation. Given that phospho-activated ERK represents only a few percent of total cellular ERK, 57 trafficking of this component to a subset of mitochondria may not be detected by standard biochemical fractionation methods.…”

Section: Discussionmentioning

confidence: 84%

“…32,33 Treatment of dopaminergic cells with 6-OHDA elicits robust activation of ERK1/2, and pharmacological inhibition of ERK activation enhances neuronal survival. 34,35 Interestingly, 6-OHDA elicits a delayed phase of mitochondrial ROS production 35 that is associated with increased mitochondrial ERK activation. 26,35 The potential function(s) of mitochondrially localized ERK activation during neuronal injury are still undefined.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress

Dagda¹,

Zhu²,

Kulich³

et al. 2008

Autophagy

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241

225

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induce mitophagy to a degree comparable with that elicited by 6-OHDA, while constitutively active ERK2 (ERK2-CA) had a greater effect. We developed green fluorescent protein (GFP) fusion constructs of WT, CA, and kinase-deficient (KD) ERK2 to study the role of ERK2 localization in regulating mitophagy and cell death. Under basal conditions, cells transfected with GFP-ERK2-WT or GFP-ERK2-CA, but not GFP-ERK2-KD, displayed discrete cytoplasmic ERK2 granules of which a significant fraction colocalized with mitochondria and markers of autophagolysosomal maturation. The colocalizing GFP-ERK2/mitochondria granules are further increased by 6-OHDA and undergo autophagic degradation, as bafilomycin-A, an inhibitor of autolysosomal degradation, robustly increased their detection. Interestingly, increasing ERK2-WT or ERK2-CA expression was sufficient to promote comparable levels of macroautophagy as assessed by analysis of the autophagy marker microtubule-associated protein 1 light chain 3 (LC3). In contrast, the level of mitophagy was more tightly correlated with ERK activity levels, potentially explained by the greater localization of ERK2-CA to mitochondria compared to ERK2-WT. These data indicate that mitochondrial localization of ERK2 activity is sufficient to recapitulate the effects of 6-OHDA on mitophagy and autophagic cell death.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress

Dagda¹,

Zhu²,

Kulich³

et al. 2008

Autophagy

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241

225

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“…Moreover, recent research suggests that mitochondrial cytochromes could also oxidize HE to a dimeric product [8]. The probe (MitoSOX ™ Red) is being used in the detection and quantitation of mitochondria-generated superoxide [9][10][11]. As mitochondria are enriched with cyt c 3+ (0.1 to 5 mM) [12,13] within the intermembrane compartment, we decided to investigate this reaction in detail.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome c-mediated oxidation of hydroethidine and mito-hydroethidine in mitochondria: Identification of homo- and heterodimers

Zielonka

Srinivasan

Hardy

et al. 2008

Free Radical Biology and Medicine

134

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Here we report that ferricytochrome c (cyt c 3+ ) induces oxidation of hydroethidine (HE) and mitochondria-targeted hydroethidine (Mito-HE or MitoSOX ™ Red) forming highly characteristic homo-and heterodimeric products. Using a HPLC-electrochemical (EC) method, several products were detected from cyt c 3+ -catalyzed oxidation of HE and Mito-HE and characterized by mass spectrometry and NMR techniques as follows: homodimers (HE-HE, E + -E + ; Mito-HE-Mito-HE, Mito-E + -Mito-E + ) and heterodimers (HE-E + and Mito-HE-Mito-E + ), as well as the monomeric ethidium (E + ) and mito-ethidium (Mito-E + ). Similar products were detected when HE and Mito-HE were incubated with mitochondria. In contrast, mitochondria depleted of cyt c 3+ were much less effective in oxidizing HE or Mito-HE to corresponding dimeric products. Unlike E + or Mito-E + , the dimeric analogs (E + -E + and Mito-E + -Mito-E + ) were not fluorescent. Superoxide ( ) or Fremy's salt react with Mito-HE to form a product, 2-hydroxy-mito-ethidium (2-OH-Mito-E + ) that was detected by HPLC. We conclude that HPLC-EC but not the confocal and fluorescence microscopy is a viable technique for measuring superoxide and cyt c 3+ -dependent oxidation products of HE and Mito-HE in cells. Superoxide detection using HE and Mito-HE could be severely compromised due to their propensity to undergo oxidation.

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“…We also found that 6-OHDA increased the phosphorylation of MAP kinases such as ERK1/2 ( Fig. 6; Kulich et al, 2007), whereas the phosphoylation of Akt was decreased in a dose-dependent manner compared to the control ( Fig. 7; Jiang and Yu, 2005).…”

Section: Discussionmentioning

confidence: 54%

Neuroprotective Effects of Carpinus tschonoskii MAX on 6-Hydroxydopamine-Induced Death of PC12 Cells

Kim¹,

Kim

Kang³

et al. 2010

Biomolecules and Therapeutics

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-The present study investigated the neuroprotective effect of Carpinus tschonoskii MAX and its intracellular protective mechanism on 6-hydroxydopamine (6-OHDA)-induced oxidative damage in PC12 cells. We found that pretreatment of PC12 cells with C. tschonoskii extract significantly inhibited the cell death induced by 6-OHDA in a dose dependent manner. C. tschonoskii extract decreased 6-OHDA-induced apoptotic events such as chromatin condensation, DNA fragmentation, the decrease of Bcl-2/Bax ratio, caspase-3 activation and PARP cleavage. C. tschonoskii extract also reduced generation of 6-OHDA-induced reactive oxygen species and nitric oxide. Furthermore, C. tschonoskii extract up-regulated the myocyte enhancer factor 2 D (MEF2D), a critical transcription factor for neuronal survival, and Akt activity, whereas it inhibited the activity of ERK1/2 and JNK. The results suggest that C. tschonoskii extract decreases 6-OHDA-induced oxidative stress and could prevent PC12 cell apoptosis induced by 6-OHDA via the up-regulation of MEF2D and Akt activity, and thus may have application in developing therapeutic agents for Parkinson's disease.

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6-Hydroxydopamine induces mitochondrial ERK activation

Cited by 84 publications

References 83 publications

Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress

Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress

Cytochrome c-mediated oxidation of hydroethidine and mito-hydroethidine in mitochondria: Identification of homo- and heterodimers

Neuroprotective Effects of Carpinus tschonoskii MAX on 6-Hydroxydopamine-Induced Death of PC12 Cells

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