Inhibition of mitochondrial calcium uptake 1 in Drosophila neurons

Pg, M'Angale; Staveley, Brian E.

doi:10.4238/gmr16019436

Cited by 11 publications

(2 citation statements)

References 31 publications

(49 reference statements)

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“…In D. melanogaster , the CG4495 gene was identified as putative MICU1 homolog based on the high similarity of essential domains. Silencing of MICU1 in dopaminergic neurons caused shortening of life span and impaired climbing ability, the latter worsened with age (48). …”

Section: Mcu: Molecular Structure and Activity Regulationmentioning

confidence: 99%

Structure, Activity Regulation, and Role of the Mitochondrial Calcium Uniporter in Health and Disease

2017

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Mitochondrial Ca2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca2+ signaling in pathophysiology have been favored by the identification of the genes encoding the mitochondrial calcium uniporter (MCU) and its regulatory subunits. Thus, research carried on in the last years on one hand has determined the structure of the MCU complex and its regulation, on the other has uncovered the consequences of dysregulated mitochondrial Ca2+ signaling in cell and tissue homeostasis. Whether mitochondrial Ca2+ uptake can be exploited as a weapon to counteract cancer progression is debated. In this review, we summarize recent research on the molecular structure of the MCU, the regulatory mechanisms that control its activity and its relevance in pathophysiology, focusing in particular on its role in cancer progression.

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Section: Mcu: Molecular Structure and Activity Regulationmentioning

confidence: 99%

Structure, Activity Regulation, and Role of the Mitochondrial Calcium Uniporter in Health and Disease

2017

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“…These data suggest a greater role for basal [Ca 2+ ]mt in proper development compared to the role of activity-induced mitochondrial Ca 2+ uptake. In drosophila, MICU1-KO led to a decreased survival rate, impaired locomotor activity, and defects in neuronal development in the eye [155]. Overexpressing the drosophila Bcl2 homolog, Buffy, rescued the MICU1-KO phenotype, suggesting that MICU1-KO led to an increase in cell death.…”

Section: In Vivo Regulation Of Auxiliary Proteinsmentioning

confidence: 98%

Molecular mechanisms and functions of mitochondrial calcium transport in neurons

Rysted¹

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Thesis Supervisor: Professor Yuriy Usachev Copyright by JACOB EUGENE RYSTED 2018 All Rights Reserved ii It's great to learn, cause knowledge is power! -Schoolhouse Rock iii *oh, be joyful* -Trying to iv ACKNOWLEDGEMENTS There are many individuals I would like to thank for their help and inspiration over the years that have helped me in completing this work. To my mentor, Yuriy Usachev, whose patience and guidance has helped immeasurably with my development as a scientist as well as increasing my fascination with science. To the entire Usachev lab, whose comraderie made life so much brighter. To Zhihong Lin, Aswini Gnanasekaran, and Leonid Shutov whose knowledge and expertise in scientific techniques helped me greatly in developing my repertoire as well as being great people to talk to. To Charles Warwick, Grant Walters, and Alex Keyes who allowed me to bounce ideas off of them and whose companionship made the lab a great place to go to everyday. I'd also like to thank our tireless undergraduate students that kept the lab from falling apart. To the people in the neuroscience program and pharmacology department that created a great environment for scientific exploration. Lastly, I'd like to thank my mother and father who have always believed in me even through turbulent times in my life. To the mice, I'm sorry we've had such a rocky relationship, but I have always had a fondness for you. To my mother, thank you for helping to guide me to the career path that I have fallen in love with, you were right about me for all those years. To my father, thank you for guiding me through life's struggles and always being a person that I can always to depend on. v ABSTRACT During neuronal activity mitochondria alter cytosolic Ca 2+ signaling by buffering then releasing Ca 2+ in the cytosol. This calcium transport by mitochondria affects the amplitude, duration, and spacial profile of the Ca 2+ 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 Ca 2+ uniporter) was the protein responsible for mitochondrial Ca 2+ uptake. Using a genetic knockout (KO) mouse model for the mitochondrial Ca 2+ uniporter (MCU) my research investigated the role of MCU in neuronal function. In cultured central and peripheral neurons, MCU-KO significantly reduced mitochondrial Ca 2+ uptake while significantly increasing the amplitude of the cytosolic Ca 2+ 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 Ca 2+ uptake, my research also investigated the mechanisms involved in mitochondrial Ca 2...

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Mitochondrial calcium uptake in organ physiology: from molecular mechanism to animal models

Mammucari

Raffaello

Reane

et al. 2018

Pflugers Arch - Eur J Physiol

127

124

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Mitochondrial Ca2+ is involved in heterogeneous functions, ranging from the control of metabolism and ATP production to the regulation of cell death. In addition, mitochondrial Ca2+ uptake contributes to cytosolic [Ca2+] shaping thus impinging on specific Ca2+-dependent events. Mitochondrial Ca2+ concentration is controlled by influx and efflux pathways: the former controlled by the activity of the mitochondrial Ca2+ uniporter (MCU), the latter by the Na+/Ca2+ exchanger (NCLX) and the H+/Ca2+ (mHCX) exchanger. The molecular identities of MCU and of NCLX have been recently unraveled, thus allowing genetic studies on their physiopathological relevance. After a general framework on the significance of mitochondrial Ca2+ uptake, this review discusses the structure of the MCU complex and the regulation of its activity, the importance of mitochondrial Ca2+ signaling in different physiological settings, and the consequences of MCU modulation on organ physiology.

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Inhibition of mitochondrial calcium uptake 1 in Drosophila neurons

Cited by 11 publications

References 31 publications

Structure, Activity Regulation, and Role of the Mitochondrial Calcium Uniporter in Health and Disease

Structure, Activity Regulation, and Role of the Mitochondrial Calcium Uniporter in Health and Disease

Molecular mechanisms and functions of mitochondrial calcium transport in neurons

Mitochondrial calcium uptake in organ physiology: from molecular mechanism to animal models

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