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dc.contributor.authorGall, Jonathan M.en_US
dc.date.accessioned2015-08-04T20:21:47Z
dc.date.available2015-08-04T20:21:47Z
dc.date.issued2012
dc.date.submitted2012
dc.identifier.other(ALMA)contemp
dc.identifier.urihttps://hdl.handle.net/2144/12392
dc.descriptionThesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.en_US
dc.description.abstractMitochondrial injury and apoptosis promote organ failure after ischemic acute kidney injury (AKI), a common cause of morbidity and mortality. In these studies, we propose that hexokinase (HK), mitofusin 2 (MFN2) and Bax, key mitochondrial associated proteins, modulate apoptotic cell death and organ function after ischemia. In the kidney, HKI and HKII isoforms both possess mitochondrial localization sequences. In vivo ischemia reduced murine proximal tubule HKII content and caused mitochondrial HKII dissociation. In cultured renal epithelial cells, expression of HKI or II significantly improved survival after ATP depletion, an in vitro model of ischemia, without preventing Bax activation or reducing mitochondrial fragmentation, a determinant of organelle sensitivity to injury. HKII over-expression increased mitochondrial associated HKII during stress and decreased mitochondrial Bax accumulation, a major cause of outer membrane permeabilization and apoptosis, suggesting that HK improves renal cell survival by antagonizing Sax-mediated injury. Deficiency of MFN2, a pro-fusion protein, caused mitochondrial fragmentation in primary proximal tubule cells without altering baseline or maximal oxygen consumption rate, or cell apoptosis. However, MFN2 deficiency significantly increased mitochondrial Bax accumulation and exacerbated mitochondrial outer membrane injury after stress. In the mouse, whole kidney MFN2 knockout caused severe mitochondrial fragmentation in renal epithelial cells. However, despite a small (20%) decrease in nephron number compared to littermate controls, newborn knockouts exhibited normal tubular and organ function. Surprisingly, proximal tubule specific MFN2 knockouts were also protected from renal ischemia. Although histologic injury scores as well as levels of apoptosis and necrosis, were similar, renal function and animal survival were significantly higher in proximal tubule specific MFN2 knockout mice at 24 and 48 hours post-ischemia. Interestingly, cortical oxidant stress was halved while cortical proliferation was nearly 4 times higher in proximal tubule knockouts compared to control, suggesting that MFN2 deficiency promotes organ recovery and survival after ischemia by enhancing proximal epithelial cell growth. While HK and MFN2 modulate Bax-mediated mitochondrial injury and apoptosis, "off-target" effects of MFN2 on renal cell proliferation ameliorate ischemia-reperfusion injury. These studies highlight the role of Bax-mediated mitochondrial injury in ischemic organ failure and suggest new targets for both attenuating injury and promoting organ recovery.en_US
dc.language.isoen_US
dc.publisherBoston Universityen_US
dc.titleHexokinase and mitofusin 2: mitochondrial modulators of apoptosis in ischemic acute kidney injuryen_US
dc.typeThesis/Dissertationen_US
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineMolecular Medicineen_US
etd.degree.grantorBoston Universityen_US


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