P7	Role of mitochondrial calcium homeostasis in energy metabolism and neuroprotection

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The figure above shows primary rat retinal ganglion cells that have been infected with a mCherry-expressing recombinant adeno-associated virus.

Project 7 shares the rat model of optic neuritis/EAE with project 3 (Fairless/Draguhn; Neurology Heidelberg/Physiology Heidelberg) and measurement of visual function with project 1 (Diem/Flockerzi; Neurology Heidelberg/Pharmacology Homburg) in order to investigate changes in mitochondrial calcium homeostasis and its relation to neurodegeneration.

Neuronal oxygen consumption will be investigated with a newly developed method of measuring mitochondrial respiration.

Analysing the coupling between neuronal activity and mitochondrial ATP production as proposed here is a central issue, which addresses the recent hypothesis that the signs of hypoxia in MS could effectively be the signs of energy insufficiency. Genetically encoded mitochondria-targeted calcium indicators will be used to visualize mitochondrial calcium signals in retinal ganglion cells during optic neuritis. Ready-to-use viral particles will be developed for project 5 (Schmitz; Anatomy Homburg) in order to collaboratively investigate the role of mitochondrial calcium buffering in synaptic signaling. Restoring mitochondrial calcium homeostasis by manipulating mitochondrial calcium uniporter expression and function will be tested as an approach to achieve neuroprotection. In collaboration with project 2 (Freichel/Friese; Pharmacology Heidelberg/Neuroimmunology Hamburg) the impact of TRPC3 on calcium influx into mitochondria during EAE will be studied with specific antibodies available from the Flockerzi group.

PrincipalInvestigators

Publications

Ahlgren H, Bas-Orth C, Freitag HE, Hellwig A, Ottersen OP, Bading H (2014) The nuclear calcium signaling target, Activating Transcription Factor 3 (ATF3), protects against dendrotoxicity and facilitates the recovery of synaptic transmission after an excitotoxic insult. J Biol Chem 289:9970-9982

Bading H (2013) Nuclear Calcium Signaling in the Regulation of Brain Function. Nat Rev Neurosci 14:593-608

Bas-Orth C, Bading H (2013) The divergence-convergence model of acquired neuroprotection. Mech Dev 130: 396-401

Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11:682-696

Hardingham GE, Fukunaga Y, Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5:405-414

Lau D, Bading H (2009) Synaptic activity-mediated suppression of p53 and induction of nuclear calcium-regulated neuroprotective genes promote survival through inhibition of mitochondrial permeability transition. J Neurosci 29: 4420-4429

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 transcriptionally repressed by neuroprotective nuclear calcium signals. Nat commun 4:2034

Zhang SJ, Buchthal B, Lau D, Hayer S, Dick O, Schwaninger M, Veltkamp R, Zou M, Weiss U, Bading H (2011) A signaling cascade of nuclear calcium–CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage. J Neurosci 31:4978-4990

Zhang SJ, Steijaert MN, Lau D, Schütz G, Delucinge-Vivier C, Descombes P, Bading H (2007) Decoding NMDA receptor signaling: identification of genomic programs specifying neuronal survival and death. Neuron 53:549-562

Zhang SJ, Zou M, Lu L, Lau D, Ditzel DA, Delucinge-Vivier C, Aso Y, Descombes P, Bading H (2009) Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity. PLoS Genet 5: e1000604

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Role of mitochondrial calcium homeostasis in energy metabolism and neuroprotection

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Prof. Dr.

Hilmar Bading