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The Downstream Targets of Complex I ...

Kim, Helena Kyunghee.

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The Downstream Targets of Complex I Dysfunction in Bipolar Disorder.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Downstream Targets of Complex I Dysfunction in Bipolar Disorder./
Author:	Kim, Helena Kyunghee.
Description:	180 p.
Notes:	Source: Dissertation Abstracts International, Volume: 77-06(E), Section: B.
Contained By:	Dissertation Abstracts International77-06B(E).
Subject:	Pharmacology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3743312
ISBN:	9781339359823

The Downstream Targets of Complex I Dysfunction in Bipolar Disorder.
Kim, Helena Kyunghee.

The Downstream Targets of Complex I Dysfunction in Bipolar Disorder. - 180 p.

Source: Dissertation Abstracts International, Volume: 77-06(E), Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2015.

Mitochondrial complex I dysfunction is consistently reported in bipolar disorder (BD), implicating its role in increased oxidative stress. Therefore, the overall aim of my PhD was to examine potential downstream targets of complex I dysfunction in BD. First, microarray studies examining complex I subunits in patients with BD or schizophrenia were re-evaluated to examine if complex I defect was specific to BD. Results revealed that complex I subunits that are involved in the electron transfer process are decreased only in patients with BD, suggesting that oxidative stress from complex I dysfunction may be specific to BD. Next, using post-mortem brain, I confirmed lower levels of complex I and its subunit, NDUFS7, in the frontal cortex of patients with BD, supporting the role of complex I dysfunction in the pathophysiology of BD. As an extension of a post-mortem brain study from our group demonstrating the mitochondria and the synapse as targets of oxidative stress, I first examined downstream targets of complex I dysfunction in the post-mortem brain, focusing on the mitochondria and the synapse. To demonstrate the mitochondria as a target of complex I dysfunction, I measured the activation of the NLRP3-inflammasome, which is a marker of mitochondrial oxidative stress. Results revealed that increased activation of the NLRP3-inflamamsome may be specific to BD, suggesting that mitochondria may be a target of complex I dysfunction. To examine the synapse as a target of complex I defect, I measured oxidative modifications to the dopaminergic synapse as increased dopamine signaling is known to underlie mania. Oxidative modifications to dopaminergic proteins, the dopamine transporter and tyrosine hydroxylase, were altered in the post-mortem prefrontal cortex of patients with BD, demonstrating the synapse as another potential target of complex I dysfunction in BD. Downstream targets of complex I dysfunction were further explored in cell models, allowing us to directly inhibit the electron transfer process of complex I using rotenone. The effect of lithium was also tested as it is uniquely used for the treatment of BD and therefore allows us to assess if the observed alterations may be relevant to BD pathology. Inhibiting complex I with rotenone increased protein oxidation and nitration, and caused an increase in methylation and hydroxymethylation of DNA. Moreover, lithium pretreatment was able to decrease these alterations, suggesting that they may be downstream targets of complex I defect in BD. Together, these studies suggest that complex I dysfunction may be specific to BD, and that it may play an important role in the pathophysiology of this disease.

ISBN: 9781339359823Subjects--Topical Terms:

634543
Pharmacology.

The Downstream Targets of Complex I Dysfunction in Bipolar Disorder.
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520 $a Mitochondrial complex I dysfunction is consistently reported in bipolar disorder (BD), implicating its role in increased oxidative stress. Therefore, the overall aim of my PhD was to examine potential downstream targets of complex I dysfunction in BD. First, microarray studies examining complex I subunits in patients with BD or schizophrenia were re-evaluated to examine if complex I defect was specific to BD. Results revealed that complex I subunits that are involved in the electron transfer process are decreased only in patients with BD, suggesting that oxidative stress from complex I dysfunction may be specific to BD. Next, using post-mortem brain, I confirmed lower levels of complex I and its subunit, NDUFS7, in the frontal cortex of patients with BD, supporting the role of complex I dysfunction in the pathophysiology of BD. As an extension of a post-mortem brain study from our group demonstrating the mitochondria and the synapse as targets of oxidative stress, I first examined downstream targets of complex I dysfunction in the post-mortem brain, focusing on the mitochondria and the synapse. To demonstrate the mitochondria as a target of complex I dysfunction, I measured the activation of the NLRP3-inflammasome, which is a marker of mitochondrial oxidative stress. Results revealed that increased activation of the NLRP3-inflamamsome may be specific to BD, suggesting that mitochondria may be a target of complex I dysfunction. To examine the synapse as a target of complex I defect, I measured oxidative modifications to the dopaminergic synapse as increased dopamine signaling is known to underlie mania. Oxidative modifications to dopaminergic proteins, the dopamine transporter and tyrosine hydroxylase, were altered in the post-mortem prefrontal cortex of patients with BD, demonstrating the synapse as another potential target of complex I dysfunction in BD. Downstream targets of complex I dysfunction were further explored in cell models, allowing us to directly inhibit the electron transfer process of complex I using rotenone. The effect of lithium was also tested as it is uniquely used for the treatment of BD and therefore allows us to assess if the observed alterations may be relevant to BD pathology. Inhibiting complex I with rotenone increased protein oxidation and nitration, and caused an increase in methylation and hydroxymethylation of DNA. Moreover, lithium pretreatment was able to decrease these alterations, suggesting that they may be downstream targets of complex I defect in BD. Together, these studies suggest that complex I dysfunction may be specific to BD, and that it may play an important role in the pathophysiology of this disease.
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