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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 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

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