A UNIQUE MITOCHONDRIAL BIOENERGETIC PATHWAY UNDERLIES ACUTE MYELOID LEUKEMIA SURVIVAL AND CHEMORESISTANCE

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dc.contributor.advisorFisher-Wellman, Kelsey H
dc.contributor.authorHagen, James T
dc.contributor.departmentPhysiology
dc.date.accessioned2024-01-16T17:35:39Z
dc.date.created2023-12
dc.date.issued2023-12-01
dc.date.submittedDecember 2023
dc.date.updated2024-01-11T18:54:24Z
dc.degree.departmentPhysiology
dc.degree.disciplinePHD-Biomedical Sciences
dc.degree.grantorEast Carolina University
dc.degree.levelDoctoral
dc.degree.namePh.D.
dc.description.abstractIn his early research on cancer cell metabolism, Otto Warburg made the hypothesis that the respiration of cancer cells has become damaged. The insult to cancer cell respiration, Warburg proposed, was either 1) a decrease in oxygen consumption, or 2) with undiminished oxygen consumption, the coupling of respiration and ATP synthesis has become broken. Herein, using multiple models of acute myeloid leukemia (AML) (i.e., chemosensitive and chemoresistant), we present evidence that supports the early hypothesis of Otto Warburg. Specifically, we discovered that 1) AML mitochondria present with defects in respiration that are masked by increases in mitochondrial content and 2) under basal conditions, AML mitochondria consume, rather than synthesize, ATP. The ATP consumption of AML cells confers a survival advantage and poises AML cells to participate in a futile cycle that mimics an alternating current circuit model. In chapter I, we provide a background on acute myeloid leukemia bioenergetics that establishes the groundwork for the research outlined in this dissertation. Specifically, our previous research discovered that relative to normal blood cells, AML cells are characterized by two important mitochondrial phenotypes: 1) AML cells present with deficiencies in oxidative phosphorylation (i.e., OxPhos) that are more pronounced in the context of chemoresistant disease; and, 2) AML import extramitochondrial ATP into the mitochondrial matrix space where it inhibits respiratory flux. In Chapter II, we discovered that, universally, the AML mitochondrion presents with 1) reductions in respiratory flux, driven by intrinsic lesions in the electron transport system, that were associated with 2) a utilization of ATP synthase as an F1-ATPase proton pump to sustain the mitochondrial membrane potential. Sustaining polarization across the inner mitochondrial membrane via F1-ATPase activity conferred chemoresistance to AML. Importantly however, chemoresistant AML were re-sensitized to chemotherapy when F1-ATPase mediated polarization was disrupted using mitochondrial-targeted lipophilic small molecules. In Chapter III, we discovered that reactivation of AML OxPhos induces BAX-independent cytotoxicity that, based on unpublished data in Chapter IV, appears to involve cytotoxic ROS production. Collectively, this dissertation proposes a unique model of AML mitochondrial bioenergetics where ATP consumption, rather than ATP synthesis, supports AML survival and confers resistance to chemotherapy. Furthermore, this dissertation presents a novel AML-specific mitochondrial pathway that can be selectively targeted by 1) disrupting F1-ATPase mediated polarization of the mitochondrial membrane, or 2) reactivating AML OxPhos.
dc.embargo.lift2025-12-01
dc.embargo.terms2025-12-01
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/10342/13270
dc.language.isoen
dc.publisherEast Carolina University
dc.subjectacute myeloid leukemia
dc.subjectaml
dc.subjectatp synthase
dc.subjectf1-atpase
dc.subjectvenetoclax
dc.subjectchemoresistance
dc.subjectros
dc.subjectoxphos
dc.subjectoxidative phosphorylation
dc.subjectdephox
dc.subjectdephosphorylative oxidation
dc.titleA UNIQUE MITOCHONDRIAL BIOENERGETIC PATHWAY UNDERLIES ACUTE MYELOID LEUKEMIA SURVIVAL AND CHEMORESISTANCE
dc.typeDoctoral Dissertation
dc.type.materialtext

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