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dc.contributor.authorEscudero, Silvia
dc.date.accessioned2019-08-09T08:55:01Z
dash.embargo.terms2019-05-01
dc.date.created2017-05
dc.date.issued2017-05-11
dc.date.submitted2017
dc.identifier.citationEscudero, Silvia. 2017. Direct Regulation of Mitochondrial Fatty Acid Oxidation by Anti-Apoptotic MCL-1. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41140604*
dc.description.abstractApoptosis is a form of programmed cell death essential to normal development and tissue homeostasis. BCL-2 family proteins are key regulators of the apoptotic pathway and control the life-death decision rendered by cells in response to stress. Localized mainly at the outer mitochondrial membrane, BCL-2 family proteins engage in a variety of heterodimeric and homooligomeric protein interactions, mediated by their conserved BCL-2 Homology (BH) domains, to determine cell fate. MCL-1 is a member of the BCL-2 family and regulates cell death by exerting potent anti-apoptotic activity. At the mitochondria, MCL-1 neutralizes pro-apoptotic BCL-2 family members, including NOXA, PUMA, BIM, and BAK, such that its pathologic overexpression contributes to the development and chemoresistance of many human cancers. Emerging data underscore that MCL-1 has unique attributes among BCL-2 anti-apoptotic proteins with respect to both amino acid composition and function. For example, unlike its anti-apoptotic homologues, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in organism homeostasis. Thus, to explore novel mechanistic role(s) of MCL-1, we undertook an exploratory proteomic study to uncover potential targets of the MCL-1 BH3 domain. Here, we report that MCL-1, and specifically its mitochondrial matrix isoform, directly engages very long chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid β-oxidation pathway. The interaction is mediated by the α-helical MCL-1 BH3 domain, which binds VLCAD at a surface groove adjacent to the enzyme active site. Deletion of endogenous Mcl-1 impairs fatty acid β-oxidation, resulting in selective accumulation of long-chain fatty acylcarnitines, as seen in VLCAD-deficient patients. Our identification of a BH3-mediated interaction between MCL-1 and VLCAD reveals a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.
dc.description.sponsorshipMedical Sciences
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectMCL-1
dc.subjectBCL-2 family
dc.subjectapoptosis
dc.subjectmitochondria
dc.subjectVLCAD
dc.subjectfatty acid metabolism
dc.subjectβ-oxidation
dc.subjectstapled peptide
dc.subjectα-helix
dc.titleDirect Regulation of Mitochondrial Fatty Acid Oxidation by Anti-Apoptotic MCL-1
dc.typeThesis or Dissertation
dash.depositing.authorEscudero, Silvia
dash.embargo.until2019-05-01
dc.date.available2019-08-09T08:55:01Z
thesis.degree.date2017
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.contributor.committeeMemberSpiegelman, Bruce
dc.contributor.committeeMemberZetter, Bruce
dc.contributor.committeeMemberSabatini, David
dc.type.materialtext
thesis.degree.departmentMedical Sciences
thesis.degree.departmentMedical Sciences
dash.identifier.vireo
dc.identifier.orcid0000-0002-0499-6883
dash.author.emailsilv.escudero@gmail.com


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