• About
    • Login
    View Item 
    •   Institutional Repository Home
    • Electronic Theses and Dissertations
    • Electronic Theses and Dissertations
    • View Item
    •   Institutional Repository Home
    • Electronic Theses and Dissertations
    • Electronic Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of Institutional RepositoryCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsDepartmentThis CollectionBy Issue DateAuthorsTitlesSubjectsDepartment

    My Account

    LoginRegister

    Bid homeostatically regulates mitochondrial cristae structure and necrotic cell death to protect against cardiac disease and bone marrow failure

    Salisbury-Ruf, Christi Therese
    : https://etd.library.vanderbilt.edu/etd-03252019-195555
    http://hdl.handle.net/1803/15398
    : 2019-03-27

    Abstract

    The Bcl-2 family protein Bid was originally characterized as a cytochrome c releasing factor during intrinsic apoptotic death. We and others noted that Bid is localized to the mitochondria in the absence of cell death. Bid-/- myeloid progenitors paradoxically display decreased viability in vitro. We took a multidisciplinary approach to determine how mitochondrial Bid impacts survival. Firstly, Bid-/- myeloid progenitor cells and cardiomyocytes revealed a significant decrease in mitochondrial cristae number, perturbation of structure, and consequently decreased respiratory function. Bid-/- cardiomyocytes have decreased ATP production, and mice are prone to cardiac dysfunction under acute stress. Two genetic approaches uncovered the impact of BID on human disease. PrediXcan analysis, which evaluates gene expression based on germline variation, uncovered decreased BID associated with myocardial infarction (MI) in multiple independent cohorts, including BioVU. Whole exome sequencing (WES) of BioVU patients identified rare coding variation within BID’s membrane binding domain associated with MI. The helix 6 single nucleotide polymorphism (SNP), M148T, identified by WES, results in loss of function when this point mutation is combined with a rescue mutant of Bid, and disrupts an interaction with the Bcl-2 protein Mcl-1, previously implicated in cristae maintenance. Importantly, regulation of cell homeostasis by Bid also extends beyond the mitochondria. Loss of Bid in the absence of Bax and Bak (VavCre +Bax F/FBak -/-Bid -/- (TKO) mice) results in bone marrow failure driven by Rip1-kinase necrosis. This bone marrow failure results in disrupted hematopoiesis and erythropoiesis that phenotypically mimics the human disorder Myelodysplastic Syndrome (MDS). Genetically altering Ripk1 function modulates inflammation and erythropoiesis in TKO mice as well as mice with loss of the epigenetic regulator TET2 (VavCre+Tet2F/F). In sum, these findings are important for understanding the role of the Bcl-2 family in mitochondrial and hematopoietic homeostasis, and highlight our complimentary approach combining cell biology with human genetics.
    Show full item record

    Files in this item

    Icon
    Name:
    Salisbury-Ruf_Dissertation_032 ...
    Size:
    62.27Mb
    Format:
    PDF
    View/Open

    This item appears in the following collection(s):

    • Electronic Theses and Dissertations

    Connect with Vanderbilt Libraries

    Your Vanderbilt

    • Alumni
    • Current Students
    • Faculty & Staff
    • International Students
    • Media
    • Parents & Family
    • Prospective Students
    • Researchers
    • Sports Fans
    • Visitors & Neighbors

    Support the Jean and Alexander Heard Libraries

    Support the Library...Give Now

    Gifts to the Libraries support the learning and research needs of the entire Vanderbilt community. Learn more about giving to the Libraries.

    Become a Friend of the Libraries

    Quick Links

    • Hours
    • About
    • Employment
    • Staff Directory
    • Accessibility Services
    • Contact
    • Vanderbilt Home
    • Privacy Policy