Regulators of mitochondrial Ca(2+) homeostasis in cerebral ischemia

Michael K E Schäfer, Annika Pfeiffer, Martin Jaeckel, Alireza Pouya, Amalia M Dolga, Axel Methner

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)

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 Ca(2+) and is fueled either by Ca(2+) from the extracellular space when triggered by neuronal activity or by Ca(2+) 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 Ca(2+) 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 Ca(2+) homeostasis in models of ischemia. The proteins include those important for the Ca(2+)-dependent motility of mitochondria and for Ca(2+) transfer from the ER to mitochondria, the tethering proteins that bring the two organelles together, inositol 1,4,5-triphosphate receptors that enable Ca(2+) release from the ER, voltage-dependent anion channels that allow Ca(2+) entry through the highly permeable outer mitochondrial membrane and the mitochondrial Ca(2+) uniporter together with its regulatory proteins that permit Ca(2+) entry into the mitochondrial matrix. Finally, we address those proteins important for the extrusion of Ca(2+) from the mitochondria such as the mitochondrial Na(+)/Ca(2+) exchanger or, if the mitochondrial Ca(2+) concentration exceeds a certain threshold, the mitochondrial permeability transition pore.

Original languageEnglish
Pages (from-to)395-405
Number of pages11
JournalCell and Tissue Research
Volume357
Issue number2
DOIs
Publication statusPublished - Aug-2014
Externally publishedYes

Keywords

  • Animals
  • Brain Ischemia
  • Cations, Divalent
  • Endoplasmic Reticulum
  • Homeostasis
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors
  • Mitochondria
  • Mitochondrial Membrane Transport Proteins
  • Neurons
  • Sodium-Calcium Exchanger
  • Voltage-Dependent Anion Channels

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