INT202218

Context Info Confidence 0.27 First Reported 2006 Last Reported 2009 Negated 0 Speculated 3 Reported most in Body Documents 4 Total Number 20 Disease Relevance 12.31 Pain Relevance 1.06

cytosol (Aco1) mitochondrion (Aco1) lyase activity (Aco1) Golgi apparatus (Aco1) endoplasmic reticulum (Aco1) RNA binding (Aco1)

Anatomy Link Frequency midbrain 3 neuronal 2 liver 1 neuron 1 heart 1 Aco1 (Mus musculus)

Pain Link Frequency Relevance Heat Inflammation 21 98.80 midbrain 306 98.56 Mechanotransduction 5 91.88 ischemia 19 86.80 Substantia nigra 17 65.00 qutenza 4 62.12 addiction 19 54.80 tolerance 6 33.60 Pain 20 29.56 Pain threshold 1 20.52

Disease Link Frequency Relevance Heat Death 1013 99.90 Parkinson's Disease 187 99.48 INFLAMMATION 21 98.80 Disease 161 98.04 Neurodegenerative Disease 68 97.60 Drug Induced Neurotoxicity 136 96.80 Stress 391 95.04 Injury 51 94.72 Targeted Disruption 70 93.12 Aging 91 92.76

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Mutation

Event

Anatomy

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Speculation

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Cells transduced with AdAcon showed a significant increase in m-aconitase mRNA (?

Positive_regulation (increase) of m-aconitase

1) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.14 Pain Relevance 0.06

To confirm that m-aconitase levels were indeed increased, m-aconitase mRNA from AdAcon transduced cells was compared to cells transduced with AdGFP.

Positive_regulation (increased) of m-aconitase

2) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.15 Pain Relevance 0.04

Astrogliosis may increase the amount of m-aconitase available for oxidative inactivation.

Spec (may) Positive_regulation (increase) of m-aconitase

3) Confidence 0.27 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 1.31 Pain Relevance 0.16

Transduction with AdAcon increases aconitase expression and activity in primary midbrain cultures

Positive_regulation (increases) of aconitase in midbrain associated with midbrain

4) Confidence 0.21 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.22 Pain Relevance 0.08

Both in vitro and in vivo studies have utilized oxidative inactivation of aconitase as an index of increased ROS levels.

Positive_regulation (inactivation) of aconitase

5) Confidence 0.20 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 1.47 Pain Relevance 0.07

Importantly, the time-course of cell death confirms that H2O2 formation and Fe2+ release occur hours prior to cell death, suggesting that oxidative inactivation of m-aconitase contributes to cell death in primary midbrain cultures.

Positive_regulation (inactivation) of m-aconitase in midbrain associated with midbrain and death

6) Confidence 0.20 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 1.03 Pain Relevance 0.05

Oxidative inactivation of m-aconitase leads to cell death

Positive_regulation (inactivation) of m-aconitase associated with death

7) Confidence 0.20 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.40 Pain Relevance 0

Our data demonstrate that oxidative inactivation of m-aconitase results in the formation of Fenton reactants in neuronal cells which provides evidence for the pathogenic mechanism in which m-aconitase not only serves as a target but also as a source of oxidants.

Positive_regulation (inactivation) of m-aconitase in neuronal

8) Confidence 0.20 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.83 Pain Relevance 0.03

Oxidative inactivation of overexpressed m-aconitase exacerbates H2O2 production and mitochondrial iron accumulation

Positive_regulation (inactivation) of m-aconitase

9) Confidence 0.20 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.07 Pain Relevance 0.09

Of note, the use of PQ2+ as a toxicant was particularly advantageous in our model because in contrast to neuron-specific toxicants such as MPP+, PQ2+ is capable of inactivating m-aconitase in both mixed neuronal/glial cultures and near pure astrocytic cultures [30].

Positive_regulation (inactivating) of m-aconitase in neuron

10) Confidence 0.20 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.58 Pain Relevance 0.05

We therefore asked whether oxidative inactivation of m-aconitase resulted in mitochondrial dysfunction and cell death 18 hrs after PQ2+ incubation in AdGFP vs.

Spec (whether) Positive_regulation (inactivation) of m-aconitase associated with parkinson's disease and death

11) Confidence 0.20 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.51 Pain Relevance 0

However, at a later time point of 18 hrs, when differences in cell viability were detected, m-aconitase overexpressing cells demonstrated a significant increase in PI+ cells in the presence of PQ2+ (Fig. 6b) suggesting that delayed cell death was resulting from m-aconitase inactivation.

Positive_regulation (resulting) of from m-aconitase associated with death

12) Confidence 0.20 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 1.00 Pain Relevance 0.04

However, whether oxidative inactivation of m-aconitase is a source of Fe2+ and H2O2 in intact neuronal cells and whether it contributes to neurotoxicity remains unknown.

Spec (whether) Positive_regulation (inactivation) of m-aconitase in neuronal associated with drug induced neurotoxicity

13) Confidence 0.20 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.76 Pain Relevance 0.08

We have previously shown that m-aconitase is oxidatively inactivated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of parkinsonism and that this correlates with an increase in chelatable mitochondrial iron in the ventral midbrain region [16].

Positive_regulation (inactivated) of m-aconitase in midbrain associated with parkinson's disease and midbrain

14) Confidence 0.18 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.89 Pain Relevance 0.05

Exacerbation of PQ2+-induced H2O2 production observed in m-aconitase overexpressing cultures presumably originates from the latter source due to increased m-aconitase available for inactivation by O2.?

Positive_regulation (increased) of m-aconitase

15) Confidence 0.18 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.39 Pain Relevance 0

The virus was tested for its ability to overexpress m-aconitase by Western blot analysis (data not shown), then grown in large scale and purified by CsCl gradient centrifugation.

Positive_regulation (overexpress) of m-aconitase

16) Confidence 0.18 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.49 Pain Relevance 0

We hypothesized that increasing the levels of m-aconitase would increase the amount of target enzyme available for oxidative inactivation leading to exacerbation of H2O2 production, Fe2+ formation and cell death.

Positive_regulation (increasing) of m-aconitase associated with death

17) Confidence 0.18 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2738973 Disease Relevance 0.18 Pain Relevance 0.07

These transgenics exhibit lower basal levels of liver mitochondrial SOD2 mRNA and protein, lower SOD2 activity levels, reduced lipid oxidation, and increased aconitase activity in mitochondria compared with wild-type mice.

Positive_regulation (increased) of aconitase in liver

18) Confidence 0.08 Published 2006 Journal Age (Dordr) Section Body Doc Link PMC2464727 Disease Relevance 0.59 Pain Relevance 0

These MCAT mice generate 25% less heart mitochondrial H2O2 and H2O2-induced aconitase inactivation, suggesting increased protection from ROS.

Positive_regulation (induced) of aconitase in heart

19) Confidence 0.07 Published 2006 Journal Age (Dordr) Section Body Doc Link PMC2464727 Disease Relevance 0.97 Pain Relevance 0.03

Therefore we compared cytoplasmic dye accumulation to the total amount of MS channel activity evoked in the presence of FM1-43 or FM3-25.

Positive_regulation (accumulation) of cytoplasmic

20) Confidence 0.03 Published 2007 Journal Mol Pain Section Body Doc Link PMC1779769 Disease Relevance 0.33 Pain Relevance 0.17

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