Advanced search options

Advanced Search Options 🞨

Browse by author name (“Author name starts with…”).

Find ETDs with:

in
/  
in
/  
in
/  
in

Written in Published in Earliest date Latest date

Sorted by

Results per page:

Sorted by: relevance · author · university · dateNew search

You searched for subject:(MICU1). Showing records 1 – 3 of 3 total matches.

Search Limiters

Last 2 Years | English Only

No search limiters apply to these results.

▼ Search Limiters


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

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

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

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 September 24, 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. 24 Sep 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 Sep 24]. 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


University of Cambridge

2. Gleeson, Tom. Genetic characterisation of the Drosophila Mitochondrial Calcium Uniporter in physiological and neurodegenerative contexts.

Degree: PhD, 2019, University of Cambridge

Neurodegenerative conditions such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are a growing medical and social burden for which no disease-modifying therapies exist, necessitating greater understanding of their underlying pathobiology. Mitochondrial health and calcium signalling have come to the fore in the study of both conditions, and mitochondrial calcium dynamics, which play a crucial role in basal metabolism and cell death, have potential to be a key player in the disease process. Though mitochondrial calcium influx had long been observed through electrophysiology and other work, the genetic basis for this process has only recently been described. The uniporter is comprised of MCU, the pore-forming component; EMRE, which coordinates the complex architecture and is required for in vivo calcium uptake; and MICU1-3, which regulate the flow of ions. Animal models have emerged for some uniporter genes, but variable effects have left their physiological role uncertain. The genetic tractability of the Drosophila melanogaster model system makes it well situated to address this, and its short lifespan facilitates investigation of diseases of aging, but it has been little utilised in the study of the uniporter. Here, I complete a full suite of genetic tools for interrogating mitochondrial calcium uniporter components conserved in Drosophila melanogaster, through molecular cloning, P-element transposition, and CRISPR-mediated targeted mutagenesis. Knockouts of MCU and EMRE, both essential for in vivo uniporter activity, are largely tolerated in the fly, though lifespan is reduced, especially for MCU. Metabolic features of these mutants also diverge. The loss of the regulatory MICU1 results in developmental lethality, preceded by organismal dysfunction. Crucially, this was not rescued by MCU or EMRE knockout, indicating the presence of a uniporter-independent role of MICU1. Knockouts of MICU3 were viable but displayed defects associated with tissues in which the gene is more expressed. In addition to characterisation of the physiological role of these genes, I crossed them to Drosophila models of neurodegenerative disease, primarily Pink1 loss. Reduction of MCU strikingly rescued Pink1-associated deficits, with more variable rescue against parkin, demonstrating some specificity for mitophagy-independent Pink1 functions. MCU loss also markedly improved a mutant amyloid expressing model of Alzheimer’s disease. As well as shedding light on the physiological requirements of mitochondrial calcium uniporter components, my work therefore argues for a subset of neurodegenerative conditions being amenable to modification of mitochondrial calcium influx. Further work should build on this potential target to attempt to ameliorate these otherwise intractable diseases.

Subjects/Keywords: mitochondria; drosophila; mcu; emre; micu1; micu3; alzheimer's disease; parkinson's disease; calcium; genetics

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

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

APA (6th Edition):

Gleeson, T. (2019). Genetic characterisation of the Drosophila Mitochondrial Calcium Uniporter in physiological and neurodegenerative contexts. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/305604

Chicago Manual of Style (16th Edition):

Gleeson, Tom. “Genetic characterisation of the Drosophila Mitochondrial Calcium Uniporter in physiological and neurodegenerative contexts.” 2019. Doctoral Dissertation, University of Cambridge. Accessed September 24, 2020. https://www.repository.cam.ac.uk/handle/1810/305604.

MLA Handbook (7th Edition):

Gleeson, Tom. “Genetic characterisation of the Drosophila Mitochondrial Calcium Uniporter in physiological and neurodegenerative contexts.” 2019. Web. 24 Sep 2020.

Vancouver:

Gleeson T. Genetic characterisation of the Drosophila Mitochondrial Calcium Uniporter in physiological and neurodegenerative contexts. [Internet] [Doctoral dissertation]. University of Cambridge; 2019. [cited 2020 Sep 24]. Available from: https://www.repository.cam.ac.uk/handle/1810/305604.

Council of Science Editors:

Gleeson T. Genetic characterisation of the Drosophila Mitochondrial Calcium Uniporter in physiological and neurodegenerative contexts. [Doctoral Dissertation]. University of Cambridge; 2019. Available from: https://www.repository.cam.ac.uk/handle/1810/305604

3. Alsufyani, Adel. Investigating dynamic spatial interactions between mitochondria and ER in living plant cells and their possible role in controlling mitochondrial calcium flux.

Degree: 2014, University of Saskatchewan

Mitochondria are dynamic organelles known primarily for their roles in oxidative metabolism and programmed cell death. Both of these processes are regulated by the mitochondrial matrix calcium concentration. Little is known about how mitochondrial calcium is regulated: no plant mitochondrial Ca2+-ATPase pumps or no mitochondrial Ca2+ channels have been identified to date. In addition, little is known concerning any physical interactions between mitochondria and endoplasmic reticulum (ER), an important cellular calcium store, and how these modulate cellular calcium fluxes. In this work stable transgenic Arabidopsis lines expressing fluorescent marker proteins were generated to allow visualisation of mitochondria and the ER in the same cells, and to measure mitochondrial calcium fluxes using aequorin. According to my results, there is a physical association between mitochondria and ER and this association cannot be disrupted by chemical treatments (latrunculin B, methyl viologen and antimycin A). As part of this work I identified an Arabidopsis gene, Mitochondrial Calcium Uptake 1 (MCU1), which encodes a protein with features that suggest a role in mitochondrial calcium dynamics. Fluorescent protein fusions of this protein demonstrated that it localizes to mitochondria. An Arabidopsis T-DNA line was identified with an insertion in MCU1. However, little effect of the insertion on transcript abundance of MCU1 was observed. Advisors/Committee Members: Todd, Chris, Gray, Gordon, Gray, Jack, Bonham-Smith, Peta, Wei, Yangdou.

Subjects/Keywords: Endoplasmic reticulum (ER)Mitochondrial Calcium Uptake 1 (MICU1)

Page 1 Page 2 Page 3

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

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

APA (6th Edition):

Alsufyani, A. (2014). Investigating dynamic spatial interactions between mitochondria and ER in living plant cells and their possible role in controlling mitochondrial calcium flux. (Thesis). University of Saskatchewan. Retrieved from http://hdl.handle.net/10388/ETD-2014-08-1688

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Alsufyani, Adel. “Investigating dynamic spatial interactions between mitochondria and ER in living plant cells and their possible role in controlling mitochondrial calcium flux.” 2014. Thesis, University of Saskatchewan. Accessed September 24, 2020. http://hdl.handle.net/10388/ETD-2014-08-1688.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Alsufyani, Adel. “Investigating dynamic spatial interactions between mitochondria and ER in living plant cells and their possible role in controlling mitochondrial calcium flux.” 2014. Web. 24 Sep 2020.

Vancouver:

Alsufyani A. Investigating dynamic spatial interactions between mitochondria and ER in living plant cells and their possible role in controlling mitochondrial calcium flux. [Internet] [Thesis]. University of Saskatchewan; 2014. [cited 2020 Sep 24]. Available from: http://hdl.handle.net/10388/ETD-2014-08-1688.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Alsufyani A. Investigating dynamic spatial interactions between mitochondria and ER in living plant cells and their possible role in controlling mitochondrial calcium flux. [Thesis]. University of Saskatchewan; 2014. Available from: http://hdl.handle.net/10388/ETD-2014-08-1688

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

.