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A2 - Geometry of calcium waves and calcium induced signals

Principal investigator(s):

Universität Heidelberg
Im Neuenheimer Feld 364
69121 Heidelberg


Projects within the BCCN:

The aim of this project was to establish a calcium-regulated transcription network that can account for the ‘divergence–convergence model’ of acquired neuroprotection, which is centered around mitochondrial calcium dynamics and bioenergetics (Bas-Orth and Bading 2012). Using gain-of-function and loss-of-function studies, individual components of the nuclear calcium-regulated gene program were tested in the context of neuronal survival, structural and functional integrity of mitochondria and metabolic plasticity (Bas-Orth et al. 2017). Key players in this process have been identified that serve to protect mitochondria against death signaling-induced breakdown of the mitochondrial membrane potential, which inevitably leads to energy failure and cell loss (Qui et al. 2013). A prime target of neuroprotective pathways is the extrasynaptic NMDA receptor, a common initiator of mitochondrial dysfunction in several neurodegenerative diseases. We have determined the transcriptome profiles of hippocampal neurons that overexpress key transcription factor components of the nuclear calcium-regulated gene pool that mediates acquired neuroprotection. The results obtained indicate the existence of common downstream gene targets suggesting that different survival-promoting transcription factors converge on a common mechanism to shield neurons against death (Bas-Orth and Bading 2012). This common mechanism appears to involve the protection of mitochondria against death signaling-induced breakdown of the mitochondrial membrane potential, which inevitably leads to energy failure. We have made viral vectors to manipulate mitochondrial sodium-calcium (lithium) exchanger Nclx. These viruses were used in primary hippocampal neurons and in other types of neurons, which were analyzed in imaging studies with respect to changes in mitochondrial calcium dynamics. Moreover, the impact of manipulating mitochondrial calcium dynamics on the mitochondrial membrane potential and cell survival/death was determined (Qui et al. 2013). The results obtained form the basis for the development of a model of neuronal mitochondrial calcium dynamics.
Such a model will be useful to analyze and predict conditions that will disrupt mitochondrial calcium handling in neurons leading to bioenergetics failure.

Participating groups:

Key publications:

Bas-Orth C, Tan YW, Lau D, Bading H (2017) Synaptic activity drives a genomic program that promotes a neuronal Warburg effect. J Biol Chem. In revision .
Qiu J, Tan YW, Hagenston AM, Martel MA, Kneisel N, Skehel PA, Wyllie DJ, Bading H, Hardingham GE (2013) Mitochondrial calcium uniporter Mcu controls excitotoxicity and is repressed by neuroprotective nuclear calcium signals. Nat. Commun. 4:2034 doi: 10.1038/ncomms3034 .
Bas-Orth C, Bading H (2012) The divergence-convergence model of acquired neuroprotection. Mech. Dev. 130, 396-401 (2012) .