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dc.contributor.advisorMootha, Vamsi
dc.contributor.advisorKahne, Daniel
dc.contributor.advisorGaudet, Rachelle
dc.contributor.advisorRapoport, Tom
dc.contributor.authorKamer, Kimberli Jean
dc.date.accessioned2019-08-08T12:54:33Z
dash.embargo.terms2018-11-01
dc.date.created2018-05
dc.date.issued2018-04-30
dc.date.submitted2018
dc.identifier.citationKamer, Kimberli Jean. 2018. Regulation of the Mitochondrial Calcium Uniporter by the MICU1/MICU2 Complex: From Biochemistry to Human Disease. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41128465*
dc.description.abstractThe mitochondrial calcium uniporter is an evolutionarily ancient calcium channel, with purported roles in many areas of cellular and organismal physiology from excitation: energetic coupling to cell death. The molecular components of the uniporter were elusive until 2010, when the inaugural component, MICU1, was identified and the remaining components were identified shortly thereafter. Here, we explore the function of both MICU1 and MICU2, ranging from protein biochemistry to human disease. We start with protein biochemistry and cellular physiology to define the role of MICU1 and MICU2 in uniporter function. Chapters 2 and 3 unveil the discovery of MICU2 and show that MICU1 and MICU2 are negative regulators of the uniporter in the intermembrane space. In Chapter 4, we show that the calcium binding affinities of MICU1 and the MICU1/MICU2 complex control the calcium concentration needed to disinhibit the uniporter. We provide further support for this model in Chapter 5, showing that MICU1 and MICU2 contribute to the selectivity of the uniporter complex, preventing manganese transport through the channel unless sufficient calcium is present. Together, these data converge on a model in which the apo (calcium-free) MICU1 and MICU2 inhibit the uniporter, keeping the channel closed; when calcium concentrations rise above ~600 nM, calcium binds to MICU1 and MICU2, allowing the channel to open. In Chapters 6 and 7, we move from biochemistry to organismal physiology. Chapter 6 discusses the cardiovascular phenotype of Micu2 knockout mice. These mice have diastolic dysfunction and, strikingly, when treated with Angiotensin II to induce hypertension, almost one-third of the knockout mice die from abdominal aortic aneurysm rupture. We explore the clinical presentation of two cousins with MICU1 deficiency in Chapter 7. Patients with MICU1 loss-of-function mutations present with a neuromuscular syndrome, including fatigue and lethargy. Calcium physiology experiments in patient fibroblasts reveal a defect in mitochondrial calcium handling suggesting matrix calcium overload, consistent with MICU1 deficiency. Great progress has been made in the past several years, but many important discoveries are still to come. Structural insights into the functional uniporter channel, the MICU1/MICU2 complex, and ultimately the holocomplex will be critical next steps. Furthermore, we need to better understand the uniporter’s role in physiology and human disease. Synthesizing our knowledge of the uniporter structure, function, and roles in pathophysiology may lead to exciting new therapeutics targeting the uniporter for both rare and common disease.
dc.description.sponsorshipChemistry and Chemical Biology
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectmitochondria
dc.subjectcalcium
dc.subjectEF hand
dc.subjectchannel regulation
dc.titleRegulation of the Mitochondrial Calcium Uniporter by the MICU1/MICU2 Complex: From Biochemistry to Human Disease
dc.typeThesis or Dissertation
dash.depositing.authorKamer, Kimberli Jean
dash.embargo.until2018-11-01
dc.date.available2019-08-08T12:54:33Z
thesis.degree.date2018
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
thesis.degree.nameDoctor of Philosophy
dc.type.materialtext
thesis.degree.departmentChemistry and Chemical Biology
thesis.degree.departmentChemistry and Chemical Biology
dash.identifier.vireo
dc.identifier.orcid0000-0001-8728-7793
dash.author.emailkjkamer1@gmail.com


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