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    Altered Mitochondrial Retrograde Signaling in Response to mtDNA Depletion or a Ketogenic Diet

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    Issue Date
    2012-12-31
    Author
    Selfridge, Jennifer Eva
    Publisher
    University of Kansas
    Format
    275 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Molecular & Integrative Physiology
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    Abstract
    Neurodegenerative diseases affect a staggering proportion of the population. Many neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease exhibit significant metabolic and bioenergetic changes both systemically and in the central nervous system. Accordingly, abnormalities in mitochondrial function are also present early in the pathogenesis of neurodegenerative diseases, leading to dysregulation of mitochondrial and metabolic signaling pathways and general neuronal dependence on anaerobic metabolism. Specifically, the electron transport chain function is reduced both systemically and in brains of individuals affected by Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. The goal of this dissertation is to better understand the mechanisms of mitochondrial retrograde signaling that may play a role in neurodegeneration. In our first study, we show that mtDNA depletion of neuroblastoma cell lines significantly alters mitochondrial retrograde signaling in such a way that promotes upregulation of respiratory chain subunits, but inhibits mitochondrial mass as a whole. Further investigation into the bioenergetic status of these mtDNA-depleted cells suggests that these non-respiratory mitochondria are unable to contribute to the cell energetically, and are thus a metabolic liability. This study provides insight into mitochondrial signaling processes that may be present in neurodegenerative disorders. Next, we examine the role of a ketogenic diet on mitochondrial signaling pathways in mouse brains. We show in this study that a ketogenic diet promotes a number of favorable metabolic changes in mice including reduction of systemic insulin resistance, an increase in the mitochondrial master regulator PGC1α and its relative PGC1β, and an increase in some elements of mitochondrial mass. This study lays mechanistic groundwork for the potential use of a ketogenic diet in neurodegenerative disorders. We then describe the generation of cybrid lines to evaluate the role of mtDNA in Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis, and normal aging. These lines have shown us that mtDNA from individuals with these various conditions confer significant mitochondrial dysfunction to their respective cell lines, and that these lines will continue to provide significant insight into the role of mtDNA and mitochondrial function in disease states and aging. Finally, we show that the pan-neurotrophin receptor p75NTR is necessary for estrogen-induced sympathetic nerve remodeling in the mouse uterus. This physiological phenomenon involves cyclical degeneration and regeneration of sympathetic nerves to uterine smooth muscle, and is an important model for studying axonal changes in normal degenerative and regenerative events.
    URI
    http://hdl.handle.net/1808/13021
    Collections
    • Dissertations [4472]
    • Molecular Biosciences Dissertations and Theses [273]

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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