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You searched for subject:(Mitochondria Calcium Uniporter). Showing records 1 – 3 of 3 total matches.

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Temple University

1. Doonan, Patrick John. Mitochondrial Calcium Uptake: LETM1 and MICU1 Are Mitochondrial Proteins That Regulate Mitochondrial Calcium Homeostasis and Cellular Bioenergetics.

Degree: PhD, 2012, Temple University

Biochemistry

Mitochondrial calcium (Ca2+) uptake has been studied for over five decades, with crucial insights into its underlying mechanisms enabled by development of the chemi-osmotic hypothesis and appreciation of the considerable voltage present across the inner mitochondrial membrane (ΔΨm) generated by proton pumping by the respiratory chain (Carafoli, 1987; Nicholls, 2005). However, the molecules that regulate mitochondrial Ca2+ uptake have only recently been identified (Jiang et. al., 2009; Perocchi et. al., 2010) and further work was needed to clarify how these molecules regulate mitochondrial Ca2+ uptake. Leucine Zipper EF hand containing Transmembrane Protein 1 (LETM1) acts as a regulator of mitochondrial Ca2+ uptake distinct from the mitochondrial Ca2+ uniporter (MCU) pathway (Jiang et. al., 2009). However, a controversy exists regarding the function of LETM1 (Nowikovsky et. al., 2004). Therefore, I asked if LETM1 played a role in mitochondrial Ca2+ uptake and if LETM1 regulated cellular bioenergetics and basal autophagy. To further characterize mitochondrial calcium uptake, we asked how Mitochondrial Calcium Uptake 1 (MICU1) regulates MCU activity by quantifying basal mitochondrial Ca2+ and MCU uptake rates in MICU1 ablated cells. The following work characterizes the molecules that regulate mitochondrial Ca2+ uptake and their mechanistic function on decoding calcium signals. Since LETM1 is the Ca2+/H+ antiporter, I hypothesize that alterations in LETM1 expression and activity will decrease mitochondrial Ca2+ uptake and will result in impaired mitochondrial bioenergetics. As a regulator of free intracellular Ca2+, mitochondrial Ca2+ uptake and the orchestra of its regulatory molecules have been implicated in many human diseases. Mitochondria act both upstream by regulating cytosolic Ca2+ concentration and as downstream effectors that respond to Ca2+ signals. Recently, LETM1 was proposed as a mitochondrial Ca2+/H+ antiporter (Jiang et. al., 2009); however characterization of the functional role of LETM1-mediated Ca2+ transfer remained unstudied. Therefore the specific aims of this project were to determine how LETM1 regulates Ca2+ homeostasis and bioenergetics under physiological settings. Secondly, this project aimed to characterize how LETM1-dependent Ca2+ signaling regulates ROS production and autophagy. The data presented here confirmed that LETM1 knockdown significantly impairs mitochondrial Ca2+ uptake. Furthermore, in-depth approaches including either deletion of EF-hand or mutation of critical EF-hand residues (D676A D688KLETM1) impaired histamine (GPCR agonist)-induced mitochondrial Ca2+ uptake. Knockdown of LETM1 resulted in bioenergetic collapse and promoted LC3-positive multilamellar vesicle formation, indicative of autophagy induction. Interestingly, knockdown of LETM1 significantly reduced complex IV but not complex I and complex II-mediated oxygen consumption rate (OCR). In contrast, cellular NADH and mitochondrial membrane potential (ΔΨm) were unaltered in both control and LETM1 knockdown…

Advisors/Committee Members: Muniswamy, Madesh, Soprano, Dianne R., Gamero, Ana, Rothberg, Brad S..

Subjects/Keywords: Biochemistry; Molecular biology; Calcium; LETM1; MICU1; Mitochondria; Mitochondria Calcium Uniporter; Uniporter

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APA (6th Edition):

Doonan, P. J. (2012). Mitochondrial Calcium Uptake: LETM1 and MICU1 Are Mitochondrial Proteins That Regulate Mitochondrial Calcium Homeostasis and Cellular Bioenergetics. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,214818

Chicago Manual of Style (16th Edition):

Doonan, Patrick John. “Mitochondrial Calcium Uptake: LETM1 and MICU1 Are Mitochondrial Proteins That Regulate Mitochondrial Calcium Homeostasis and Cellular Bioenergetics.” 2012. Doctoral Dissertation, Temple University. Accessed October 20, 2020. http://digital.library.temple.edu/u?/p245801coll10,214818.

MLA Handbook (7th Edition):

Doonan, Patrick John. “Mitochondrial Calcium Uptake: LETM1 and MICU1 Are Mitochondrial Proteins That Regulate Mitochondrial Calcium Homeostasis and Cellular Bioenergetics.” 2012. Web. 20 Oct 2020.

Vancouver:

Doonan PJ. Mitochondrial Calcium Uptake: LETM1 and MICU1 Are Mitochondrial Proteins That Regulate Mitochondrial Calcium Homeostasis and Cellular Bioenergetics. [Internet] [Doctoral dissertation]. Temple University; 2012. [cited 2020 Oct 20]. Available from: http://digital.library.temple.edu/u?/p245801coll10,214818.

Council of Science Editors:

Doonan PJ. Mitochondrial Calcium Uptake: LETM1 and MICU1 Are Mitochondrial Proteins That Regulate Mitochondrial Calcium Homeostasis and Cellular Bioenergetics. [Doctoral Dissertation]. Temple University; 2012. Available from: http://digital.library.temple.edu/u?/p245801coll10,214818

2. Houlihan, Patrick Ryan. The role of mitochondrial restructuring in neuronal calcium homeostasis and excitotoxicity.

Degree: PhD, Pharmacology, 2013, University of Iowa

Mitochondrial Ca2+ buffering is an important physiological modulator of neuronal signaling and bioenergetics, but this propensity toward Ca2+ regulation proves pathological during excitotoxic insult. Specifically, excessive mitochondrial Ca2+ uptake is a key component of glutamate toxicity within the penumbra surrounding the ischemic core following stroke. This mitochondrial toxicity and Ca2+ dyshomeostasis may be visualized in real time as delayed calcium deregulation (DCD). DCD is a predictor of neuronal, excitoxic death, and is composed of three phases: 1) an initial response; 2) a latent period of elevated, but stable cytosolic Ca2+; and 3) failure of mitochondrial Ca2+ retention, termed deregulation. The duration of the latent period is an index of neuronal resistance. Mitochondria are dynamic organelles that rapidly and reversibly undergo fission and fusion (MFF). MFF is tightly regulated by the phosphoregulation of fission inducing Drp1 at serine 656. Drp1-S656 phosphorelation is mediated by PKA/AKAP1, and it is dephosphorylated by PP2A/Bβ2. Phosphorylation of Drp1-S656 inactivates this contractile GTPase resulting in inhibition of mitochondrial fission and a shift toward elongated mitochondria. This PKA/AKAP1 dependent Drp1-S656 phosphorylation has proven to be neuroprotective. Likewise, attenuation of PP2A/Bβ2 signaling enhances neuronal survival during ischemia and excitotoxic insult. Based on the mitochondrial buffering role in excitotoxicity and MFF modulation of neuronal survival, we began investigating the role of Ca2+ buffering as a function of MFF during glutamate toxicity. Noted above, resistance to excitoticity is visualized by the duration of the DCD latent period. Overexpression of AKAP1 in cultured hippocampal neurons greatly prolonged DCD latency in a PKA dependent manner, while Bβ2 ablation prolonged DCD latency by hours. Pharmacological modulation of PKA required PDE4 inhibition to reproduce the AKAP1 observations. Preliminary experiments studying the effect of Bβ2 overexpression on matrix Ca2+ load suggests possible mechanism of MFF regulated of matrix Ca2+ accumulation. Using mtPericam DRG neurons as a model system for individual mitochondrial Ca2+ recording, we discovered impaired extrusion kinetics in mitochondria fragmented by both Drp1 and Bβ2 overexpression. Ca2+ uptake was comparable to that of control. Extreme elongation of mitochondria via dominant negative Drp1-K38A enhanced recovery. Understanding these observations, however, requires knowledge of the mitochondrial Ca2+ buffering mechanism. Mitochondrial uptake candidates include MCU and ccdc109b. Our neuronal… Advisors/Committee Members: Usachev, Yuriy M. (supervisor).

Subjects/Keywords: Calcium; Excitotoxicity; Fission; Fusion; Mitochondria; Uniporter; Pharmacology

…Mitochondrial calcium uniporter (MCU).......................................96 MCU isoform… …MCU mitochondrial calcium uniporter MEM modified eagle medium MFF mitochondrial fission… …x28;termed the mitochondrial calcium uniporter, or MCU) has been entirely speculative… …have been proposed. One area of mitochondria calcium buffering research supports a… …buffering, CBARA1 was re-termed mitochondria calcium uptake 1, MICU1. MICU1 is an IMM associated… 

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APA (6th Edition):

Houlihan, P. R. (2013). The role of mitochondrial restructuring in neuronal calcium homeostasis and excitotoxicity. (Doctoral Dissertation). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/2522

Chicago Manual of Style (16th Edition):

Houlihan, Patrick Ryan. “The role of mitochondrial restructuring in neuronal calcium homeostasis and excitotoxicity.” 2013. Doctoral Dissertation, University of Iowa. Accessed October 20, 2020. https://ir.uiowa.edu/etd/2522.

MLA Handbook (7th Edition):

Houlihan, Patrick Ryan. “The role of mitochondrial restructuring in neuronal calcium homeostasis and excitotoxicity.” 2013. Web. 20 Oct 2020.

Vancouver:

Houlihan PR. The role of mitochondrial restructuring in neuronal calcium homeostasis and excitotoxicity. [Internet] [Doctoral dissertation]. University of Iowa; 2013. [cited 2020 Oct 20]. Available from: https://ir.uiowa.edu/etd/2522.

Council of Science Editors:

Houlihan PR. The role of mitochondrial restructuring in neuronal calcium homeostasis and excitotoxicity. [Doctoral Dissertation]. University of Iowa; 2013. Available from: https://ir.uiowa.edu/etd/2522

3. Rysted, Jacob Eugene. Molecular mechanisms and functions of mitochondrial calcium transport in neurons.

Degree: PhD, Neuroscience, 2018, University of Iowa

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. Advisors/Committee Members: Usachev, Yuriy M. (supervisor).

Subjects/Keywords: calcium; mitochondria; mitochondrial calcium uniporter; NCLX; neuron; Neuroscience and Neurobiology

…x28;ccdc109b) MCUC: Mitochondrial calcium uniporter complex mPTP: mitochondrial… …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… …survival; mitochondria have the ability to alter how much Ca2+ is inside the cell, how long it… …However, if too much Ca2+ enters the mitochondria this can lead to cell death, and this… 

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Rysted, J. E. (2018). Molecular mechanisms and functions of mitochondrial calcium transport in neurons. (Doctoral Dissertation). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/6632

Chicago Manual of Style (16th Edition):

Rysted, Jacob Eugene. “Molecular mechanisms and functions of mitochondrial calcium transport in neurons.” 2018. Doctoral Dissertation, University of Iowa. Accessed October 20, 2020. https://ir.uiowa.edu/etd/6632.

MLA Handbook (7th Edition):

Rysted, Jacob Eugene. “Molecular mechanisms and functions of mitochondrial calcium transport in neurons.” 2018. Web. 20 Oct 2020.

Vancouver:

Rysted JE. Molecular mechanisms and functions of mitochondrial calcium transport in neurons. [Internet] [Doctoral dissertation]. University of Iowa; 2018. [cited 2020 Oct 20]. Available from: https://ir.uiowa.edu/etd/6632.

Council of Science Editors:

Rysted JE. Molecular mechanisms and functions of mitochondrial calcium transport in neurons. [Doctoral Dissertation]. University of Iowa; 2018. Available from: https://ir.uiowa.edu/etd/6632

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