Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93AhSOD1 mice

Vedrana Tadić; Adam Adam; Nadine Goldhammer; Janin Lautenschlaeger; Moritz Oberstadt; Ayse Malci; Thanh Tu Le; Saikata Sengupta; Beatrice Stubendorff; Silke Keiner; Otto W. Witte; Julian Grosskreutz

doi:10.1016/j.neurobiolaging.2018.11.019

Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93A^hSOD1 mice

Vedrana Tadić^*, Adam Adam, Nadine Goldhammer, Janin Lautenschlaeger, Moritz Oberstadt, Ayse Malci, Thanh Tu Le, Saikata Sengupta, Beatrice Stubendorff, Silke Keiner, Otto W. Witte, Julian Grosskreutz

^*Corresponding author for this work

14 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis is characterized by progressive death of motor neurons (MNs) with glutamate excitotoxicity and mitochondrial Ca²⁺ overload as critical mechanisms in disease pathophysiology. We used MNs from G93A^hSOD1 and nontransgenic embryonic cultures and adult mice to analyze the expression of the main mitochondrial calcium uniporter (MCU). MCU was overexpressed in cultured embryonic G93A^hSOD1 MNs compared to nontransgenic MNs but downregulated in MNs from adult G93A^hSOD1 mice. Furthermore, cultured embryonic G93A^hSOD1 were rescued from kainate-induced excitotoxicity by the Ca²⁺/calmodulin-dependent protein kinase type II inhibitor; KN-62, which reduced MCU expression in G93A^hSOD1 MNs. MCU activation via kaempferol neither altered MCU expression nor influenced MN survival. However, its acute application served as a fine tool to study spontaneous Ca²⁺ activity in cultured neurons which was significantly altered by the mutated hSOD1. Pharmacological manipulation of MCU expression might open new possibilities to fight excitotoxic damage in amyotrophic lateral sclerosis.

Original language	English
Journal	Neurobiology of Aging
Volume	75
Pages (from-to)	209-222
Number of pages	14
ISSN	0197-4580
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.11.019
Publication status	Published - 03.2019
Externally published	Yes

Funding

This research is supported by BMBF, Germany (Bundesministerium für Bildung and Forschung) in the framework of the E-RARE program (PYRAMID, 01GM1304 ) and JPND (SOPHIA, 01ED1202B ) of the European Union to JG and the Deutsche Gesellschaft für Muskelkranke e.V. (DGM) in collaboration with the German Network for Motoneuron Disease (MND-NET). Furthermore, it is supported by an ALS Young Investigator Research Scholarship by the Deutsche Gesellschaft für Muskelkranke (DGM) and a Junior Research Grant by the Medical Faculty, University of Leipzig, to MO. JL was supported by a research fellowship from the Deutsche Forschungsgemeinschaft (DFG; award LA 3609/2-1). For the technical assistance, the authors thank Svetlana Tausch and Madlen Günther.

Research Areas and Centers

Centers: Center for Neuromuscular Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.neurobiolaging.2018.11.019

Cite this

Tadić, V., Adam, A., Goldhammer, N., Lautenschlaeger, J., Oberstadt, M., Malci, A., Le, T. T., Sengupta, S., Stubendorff, B., Keiner, S., Witte, O. W., & Grosskreutz, J. (2019). Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93A^hSOD1 mice. Neurobiology of Aging, 75, 209-222. https://doi.org/10.1016/j.neurobiolaging.2018.11.019

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title = "Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93AhSOD1 mice",

abstract = "Amyotrophic lateral sclerosis is characterized by progressive death of motor neurons (MNs) with glutamate excitotoxicity and mitochondrial Ca2+ overload as critical mechanisms in disease pathophysiology. We used MNs from G93AhSOD1 and nontransgenic embryonic cultures and adult mice to analyze the expression of the main mitochondrial calcium uniporter (MCU). MCU was overexpressed in cultured embryonic G93AhSOD1 MNs compared to nontransgenic MNs but downregulated in MNs from adult G93AhSOD1 mice. Furthermore, cultured embryonic G93AhSOD1 were rescued from kainate-induced excitotoxicity by the Ca2+/calmodulin-dependent protein kinase type II inhibitor; KN-62, which reduced MCU expression in G93AhSOD1 MNs. MCU activation via kaempferol neither altered MCU expression nor influenced MN survival. However, its acute application served as a fine tool to study spontaneous Ca2+ activity in cultured neurons which was significantly altered by the mutated hSOD1. Pharmacological manipulation of MCU expression might open new possibilities to fight excitotoxic damage in amyotrophic lateral sclerosis.",

author = "Vedrana Tadi{\'c} and Adam Adam and Nadine Goldhammer and Janin Lautenschlaeger and Moritz Oberstadt and Ayse Malci and Le, \{Thanh Tu\} and Saikata Sengupta and Beatrice Stubendorff and Silke Keiner and Witte, \{Otto W.\} and Julian Grosskreutz",

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Tadić, V, Adam, A, Goldhammer, N, Lautenschlaeger, J, Oberstadt, M, Malci, A, Le, TT, Sengupta, S, Stubendorff, B, Keiner, S, Witte, OW & Grosskreutz, J 2019, 'Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93A^hSOD1 mice', Neurobiology of Aging, vol. 75, pp. 209-222. https://doi.org/10.1016/j.neurobiolaging.2018.11.019

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T1 - Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93AhSOD1 mice

AU - Tadić, Vedrana

AU - Adam, Adam

AU - Goldhammer, Nadine

AU - Lautenschlaeger, Janin

AU - Oberstadt, Moritz

AU - Malci, Ayse

AU - Le, Thanh Tu

AU - Sengupta, Saikata

AU - Stubendorff, Beatrice

AU - Keiner, Silke

AU - Witte, Otto W.

AU - Grosskreutz, Julian

PY - 2019/3

Y1 - 2019/3

N2 - Amyotrophic lateral sclerosis is characterized by progressive death of motor neurons (MNs) with glutamate excitotoxicity and mitochondrial Ca2+ overload as critical mechanisms in disease pathophysiology. We used MNs from G93AhSOD1 and nontransgenic embryonic cultures and adult mice to analyze the expression of the main mitochondrial calcium uniporter (MCU). MCU was overexpressed in cultured embryonic G93AhSOD1 MNs compared to nontransgenic MNs but downregulated in MNs from adult G93AhSOD1 mice. Furthermore, cultured embryonic G93AhSOD1 were rescued from kainate-induced excitotoxicity by the Ca2+/calmodulin-dependent protein kinase type II inhibitor; KN-62, which reduced MCU expression in G93AhSOD1 MNs. MCU activation via kaempferol neither altered MCU expression nor influenced MN survival. However, its acute application served as a fine tool to study spontaneous Ca2+ activity in cultured neurons which was significantly altered by the mutated hSOD1. Pharmacological manipulation of MCU expression might open new possibilities to fight excitotoxic damage in amyotrophic lateral sclerosis.

AB - Amyotrophic lateral sclerosis is characterized by progressive death of motor neurons (MNs) with glutamate excitotoxicity and mitochondrial Ca2+ overload as critical mechanisms in disease pathophysiology. We used MNs from G93AhSOD1 and nontransgenic embryonic cultures and adult mice to analyze the expression of the main mitochondrial calcium uniporter (MCU). MCU was overexpressed in cultured embryonic G93AhSOD1 MNs compared to nontransgenic MNs but downregulated in MNs from adult G93AhSOD1 mice. Furthermore, cultured embryonic G93AhSOD1 were rescued from kainate-induced excitotoxicity by the Ca2+/calmodulin-dependent protein kinase type II inhibitor; KN-62, which reduced MCU expression in G93AhSOD1 MNs. MCU activation via kaempferol neither altered MCU expression nor influenced MN survival. However, its acute application served as a fine tool to study spontaneous Ca2+ activity in cultured neurons which was significantly altered by the mutated hSOD1. Pharmacological manipulation of MCU expression might open new possibilities to fight excitotoxic damage in amyotrophic lateral sclerosis.

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