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1. Luongo, Timothy Scott. The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease.
Degree: PhD, 2017, Temple University
The high metabolic demand of the heart makes it essential that an efficient and tightly controlled system be in place to regulate energy production. Contractility is mediated by a variable flux in intracellular calcium (iCa2+), which is proposed to be integrated into mitochondria to regulate cardiac energetics. Moreover, mitochondrial Ca2+ (mCa2+)-overload is known to activate the mitochondrial permeability transition pore (MPTP) and induce cell death. However, the true function of cardiac mCa2+ in physiology remains unknown. Recent studies have reported that the Mcu gene encodes the channel-forming portion of the mitochondrial calcium uniporter (MCU) and is required for mCa2+ uptake (Baughman et al., 2011; De Stefani, Raffaello, Teardo, Szabo, & Rizzuto, 2011). To examine the role of mCa2+ in the heart, we generated a conditional, cardiac-specific knockout model and deleted Mcu in adult mice (Mcu-cKO). Loss of Mcu protected against myocardial ischemia-reperfusion (IR) (40 min occlusion of the left coronary artery (LCA) followed by 24h reperfusion) injury by preventing the activation of the MPTP. We observed a 45% reduction in infarct size per area-at-risk and a 65% reduction in cardiac troponin-I serum levels from 24h post-IR. In addition, while we found no baseline phenotype or change in baseline mCa2+ content, Mcu-cKO mice lacked contractile responsiveness to β-adrenergic receptor stimulation (isoproterenol infusion) as assessed by invasive hemodynamics, and, in parallel, were unable to activate mitochondrial dehydrogenases, thereby decreasing tricarboxylic acid (TCA) cycle flux and cardiac NADH. We found that Mcu-cKO mice had a 3-fold increase in pyruvate dehydrogenase (PDH) phosphorylation and a 50% decrease in PDH activity post-isoproterenol infusion. Further experimental analyses in isolated adult cardiomyocytes confirmed a lack of energetic responsiveness to acute sympathetic stress (isoproterenol failure to mediate an increase in oxidative phosphorylation capacity) supporting the hypothesis that the physiological function of the MCU in the heart is to modulate Ca2+-dependent metabolism during the ‘fight or flight’ response. However, questions still remain on how basal mCa2+ levels are regulated and if it contributes to cardiac disease. The mitochondrial sodium/calcium exchanger (mNCX) is hypothesized as the primary mechanism of mCa2+ efflux, but to date no study has confirmed its identity or function in an in vivo system (Palty et al., 2010). To investigate the role of mNCX in the heart, we generated mutant mice with loxP sites flanking exons 5-7 of the candidate gene, Slc8b1, and crossed them with a tamoxifen-inducible, cardiomyocyte-specific, αMHC-Cre mouse to delete mNCX in the adult heart (mNCX-cKO). Biophysical study of cardiomyocytes isolated from mNCX-cKO mice revealed a significant reduction in mCa2+ efflux rate. Tamoxifen-induced deletion of Slc8b1 in adult hearts caused sudden death with less than 15% of mice surviving after 10 days. Echocardiographic evaluation of mNCX-cKO…Advisors/Committee Members: Elrod, John W.;, Koch, Walter J., Madesh, Muniswamy, Houser, Steven R., Murphy, Elizabeth;.
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APA (6th Edition):
Luongo, T. S. (2017). The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,437718
Chicago Manual of Style (16th Edition):
Luongo, Timothy Scott. “The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease.” 2017. Doctoral Dissertation, Temple University. Accessed July 02, 2020. http://digital.library.temple.edu/u?/p245801coll10,437718.
MLA Handbook (7th Edition):
Luongo, Timothy Scott. “The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease.” 2017. Web. 02 Jul 2020.
Luongo TS. The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease. [Internet] [Doctoral dissertation]. Temple University; 2017. [cited 2020 Jul 02]. Available from: http://digital.library.temple.edu/u?/p245801coll10,437718.
Council of Science Editors:
Luongo TS. The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease. [Doctoral Dissertation]. Temple University; 2017. Available from: http://digital.library.temple.edu/u?/p245801coll10,437718