Role of Ca2+-dependent mitochondrial and endoplasmic reticulumdynamics for disease progression and neuroprotection in a model ofmultiple sclerosis.

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Mitochondria are integral for cellular function and survival. They generate ATP for cellular energy homeostasis, act as a Ca2+ sink and source to influence cellular Ca2+ signaling, and are key hubs for necrotic and apoptotic signaling networks. Accordingly, aberrant mitochondrial function is key to many neurodegenerative and neuroinflammatory diseases. Mitochondrial function depends on proper regulation of intra-mitochondrial Ca2+ levels, which in turn are tightly linked to cellular Ca2+ transients. Research from members of this Research Unit as well as from other labs has provided evidence for disturbed cellular Ca2+ homeostasis in multiple sclerosis. Given the tight coupling of cellular and mitochondrial Ca2+ levels, we hypothesize that mitochondrial Ca2+ dysregulation contributes to multiple sclerosis disease progression. In this project, we thus want to investigate the relationship between mitochondrial Ca2+ signaling, mitochondrial metabolic function, and neuronal degeneration in the rat experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and optic neuritis. We plan to use genetically encoded fluorescent indicators to comprehensively analyse mitochondrial Ca2+ signaling and metabolic function in acute retinal slices from control and EAE animals. These novel indicators allow dynamic and quantitative imaging with single cell and subcellular resolution and thus provide information that cannot be obtained using conventional biochemical methods. Finally, by manipulating the expression levels of recently identified mitochondrial Ca2+ transporter proteins we aim at restoring mitochondrial Ca2+ homeostasis, metabolic function, and cell survival in the EAE model of multiple sclerosis.