Date of Degree
PhD (Doctor of Philosophy)
First Committee Member
Taylor, Eric B.
Second Committee Member
Third Committee Member
Fourth Committee Member
During neuronal activity mitochondria alter cytosolic Ca2+ signaling by buffering then releasing Ca2+ in the cytosol. This calcium transport by mitochondria affects the amplitude, duration, and spacial profile of the Ca2+ signal in the cytosol of neurons. This buffering by mitochondria has been shown to affect a variety of neuronal functions including: neurotransmission, gene expression, cell excitability, and cell death. Recently, researchers discovered that the protein CCDC109A (mitochondrial Ca2+ uniporter) was the protein responsible for mitochondrial Ca2+ uptake. Using a genetic knockout (KO) mouse model for the mitochondrial Ca2+ uniporter (MCU) my research investigated the role of MCU in neuronal function. In cultured central and peripheral neurons, MCU-KO significantly reduced mitochondrial Ca2+ uptake while significantly increasing the amplitude of the cytosolic Ca2+ signal amplitude. Behaviorally, MCU-KO mice show a small but significant impairment in memory tasks: fear conditioning and Barnes maze. Using a maximal electroshock seizure threshold model of in vivo seizure activity my research found that MCU-KO significantly increases the threshold for maximal seizure activity in mice and significantly reduces seizure severity. In addition to mitochondrial Ca2+ uptake, my research also investigated the mechanisms involved in mitochondrial Ca2+ extrusion. The protein SLC8B1 (SLC24A6, NCLX) is the putative transporter responsible for the Na+/Ca2+ exchange, mitochondrial calcium extrusion. Using genetic NCLX-KO mice, our research found that in neurons NCLX contributes to cytosolic Ca2+ extrusion, but does seem to directly affect mitochondrial Ca2+ extrusion.
calcium, mitochondria, mitochondrial calcium uniporter, NCLX, neuron
xiii, 177 pages
Includes bibliographical references (pages 160-177).
Copyright © 2018 Jacob Eugene Rysted
Rysted, Jacob Eugene. "Molecular mechanisms and functions of mitochondrial calcium transport in neurons." PhD (Doctor of Philosophy) thesis, University of Iowa, 2018.