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Author
Title Molecular mechanisms and functions of mitochondrial calcium transport in neurons
URL
Publication Date
Degree PhD
Discipline/Department Neuroscience
Degree Level doctoral
University/Publisher University of Iowa
Abstract 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.
Subjects/Keywords calcium; mitochondria; mitochondrial calcium uniporter; NCLX; neuron; Neuroscience and Neurobiology
Contributors Usachev, Yuriy M. (supervisor)
Language en
Country of Publication us
Format application/pdf
Record ID oai:ir.uiowa.edu:etd-8131
Repository iowa
Date Retrieved
Date Indexed 2020-02-25
Grantor University of Iowa
Issued Date 2018-12-01 08:00:00

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Mitochondria Ca2+ Uptake Mechanism ......................................... 15 Mitochondrial Ca2+ Uniporter ........................................................ 17 Mitochondrial Ca2+ Uniporter Paralog/Isoform .............................. 20 EMRE…

…Mitochondrial calcium uniporter complex mPTP: mitochondrial permeability IMS: Inter-mitochondrial space Na+: Sodium ion NADH: Reduced nicotineamide adenine dinucleotide NCKX: K+ dependent Na+/Ca2+ exchanger NCLX: Na+/Li+/Ca2+ exchanger NCX: Na+/Ca2+ exchanger…

…PUBLIC ABSTRACT Mitochondria are known as the powerhouse of the cell, as they are the part of the cell that produces energy; however, alongside producing energy, mitochondria are also involved in processes such as Ca2+ signaling, reactive-oxygen…

…species production, and programmed cell death. For the nervous system, Ca2+ is involved in a variety of processes including electrical excitability, synaptic transmission and plasticity, gene regulation, cell death and survival; mitochondria have the…

…ability to alter how much Ca2+ is inside the cell, how long it stays elevated inside the cell, and in which compartments inside the cell it is localized. However, if too much Ca2+ enters the mitochondria this can lead to cell death, and this mechanism of…

…xi CHAPTER I: INTRODUCTION ..................................................................1 Mitochondria Function in Neurons .................................................. 3 Mitochondrial Dysfunction in Neuronal Pathology…

…6 Mitochondria in Neuronal Ca2+ Signaling ........................................ 8 Mitochondrial Ca2+ Dynamics in Neuronal Pathology ................... 11 Mitochondria and Seizure Activity ................................................. 13…

…73 Figure 2.7: Deletion of MCU significantly inhibits mitochondrial Ca2+ rate and amount of Ca2+ influx in isolated brain mitochondria .......................................................................... 75 Figure 2.8: Deletion of MCU alters…

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