Abstract
Cerebral ischemia is a key pathophysiological feature of various brain insults. Inadequate oxygen supply can manifest regionally in stroke or as a result of traumatic brain injury or globally following cardiac arrest, all leading to irreversible brain damage. Mitochondrial function is essential for neuronal survival, since neurons critically depend on ATP synthesis generated by mitochondrial oxidative phosphorylation. Mitochondrial activity depends on Ca2+ and is fueled either by Ca2+ from the extracellular space when triggered by neuronal activity or by Ca2+ released from the endoplasmic reticulum (ER) and taken up through specialized contact sites between the ER and mitochondria known as mitochondrial-associated ER membranes. The coordination of these Ca2+ pools is required to synchronize mitochondrial respiration rates and ATP synthesis to physiological demands. In this review, we discuss the role of the proteins involved in mitochondrial Ca2+ homeostasis in models of ischemia. The proteins include those important for the Ca2+-dependent motility of mitochondria and for Ca2+ transfer from the ER to mitochondria, the tethering proteins that bring the two organelles together, inositol 1,4,5-triphosphate receptors that enable Ca2+ release from the ER, voltage-dependent anion channels that allow Ca2+ entry through the highly permeable outer mitochondrial membrane and the mitochondrial Ca2+ uniporter together with its regulatory proteins that permit Ca2+ entry into the mitochondrial matrix. Finally, we address those proteins important for the extrusion of Ca2+ from the mitochondria such as the mitochondrial Na+/Ca2+ exchanger or, if the mitochondrial Ca2+ concentration exceeds a certain threshold, the mitochondrial permeability transition pore.
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We thank Darragh O’Neill for excellent proofreading.
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This work was funded by the Else-Kröner-Fresenius-Stiftung to A.M. (P28/10//A39/10) and the Deutsche Forschungsgemeinschaft (CRC1080) to A.M. and M.S. A.P. is also affiliated with the Faculty of Biology of the Johannes Gutenberg University Mainz
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Schäfer, M.K.E., Pfeiffer, A., Jaeckel, M. et al. Regulators of mitochondrial Ca2+ homeostasis in cerebral ischemia. Cell Tissue Res 357, 395–405 (2014). https://doi.org/10.1007/s00441-014-1807-y
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DOI: https://doi.org/10.1007/s00441-014-1807-y