Cell and Tissue Research

, Volume 357, Issue 2, pp 395–405 | Cite as

Regulators of mitochondrial Ca2+ homeostasis in cerebral ischemia

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


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.


Calcium Homeostasis Mitochondria Mitochondrial-associated endoplasmic reticulum membranes Cerebral ischemia Neuronal survival 



We thank Darragh O’Neill for excellent proofreading.


  1. Ajmo CT, Vernon DOL, Collier L et al (2006) Sigma receptor activation reduces infarct size at 24 hours after permanent middle cerebral artery occlusion in rats. Curr Neurovasc Res 3:89–98PubMedGoogle Scholar
  2. Aoki M, Abe K, Yoshida T et al (1995) Early immunohistochemical changes of microtubule based motor proteins in gerbil hippocampus after transient ischemia. Brain Res 669:189–196PubMedGoogle Scholar
  3. Baines CP, Kaiser RA, Sheiko T et al (2007) Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol 9:550–555. doi: 10.1038/ncb1575 PubMedCentralPubMedGoogle Scholar
  4. Basso E, Fante L, Fowlkes J et al (2005) Properties of the permeability transition pore in mitochondria devoid of cyclophilin D. J Biol Chem 280:18558–18561. doi: 10.1074/jbc.C500089200 PubMedGoogle Scholar
  5. Baughman JM, Perocchi F, Girgis HS et al (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341–345. doi: 10.1038/nature10234 PubMedCentralPubMedGoogle Scholar
  6. Báthori G, Csordás G, Garcia-Perez C et al (2006) Ca2+−dependent control of the permeability properties of the mitochondrial outer membrane and voltage-dependent anion-selective channel (VDAC). J Biol Chem 281:17347–17358. doi: 10.1074/jbc.M600906200 PubMedGoogle Scholar
  7. Bernardi P (2013) The mitochondrial permeability transition pore: a mystery solved? Front Physiol 4:95. doi: 10.3389/fphys.2013.00095 PubMedCentralPubMedGoogle Scholar
  8. Bevers MB, Neumar RW (2008) Mechanistic role of calpains in postischemic neurodegeneration. J Cereb Blood Flow Metab 28:655–673. doi: 10.1038/sj.jcbfm.9600595 PubMedGoogle Scholar
  9. Billups B, Forsythe ID (2002) Presynaptic mitochondrial calcium sequestration influences transmission at mammalian central synapses. J Neurosci 22:5840–5847PubMedGoogle Scholar
  10. Blackshaw S, Sawa A, Sharp AH et al (2000) Type 3 inositol 1,4,5-trisphosphate receptor modulates cell death. FASEB J 14:1375–1379PubMedGoogle Scholar
  11. Bonanni L, Chachar M, Jover-Mengual T et al (2006) Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain. J Neurosci 26:6851–6862. doi: 10.1523/JNEUROSCI.5444-05.2006 PubMedGoogle Scholar
  12. Boyman L, Williams GSB, Khananshvili D et al (2013) NCLX: the mitochondrial sodium calcium exchanger. J Mol Cell Cardiol 59:205–213. doi: 10.1016/j.yjmcc.2013.03.012 PubMedCentralPubMedGoogle Scholar
  13. Brookes PS, Yoon Y, Robotham JL et al (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 287:C817–C833. doi: 10.1152/ajpcell.00139.2004 PubMedGoogle Scholar
  14. Cai B, Lin Y, Xue X-H et al (2011) TAT-mediated delivery of neuroglobin protects against focal cerebral ischemia in mice. Exp Neurol 227:224–231. doi: 10.1016/j.expneurol.2010.11.009 PubMedGoogle Scholar
  15. Carafoli E, Tiozzo R, Lugli G et al (1974) The release of calcium from heart mitochondria by sodium. J Mol Cell Cardiol 6:361–371PubMedGoogle Scholar
  16. Chan ASY, Saraswathy S, Rehak M et al (2012) Neuroglobin protection in retinal ischemia. Invest Ophthalmol Vis Sci 53:704–711. doi: 10.1167/iovs.11-7408 PubMedCentralPubMedGoogle Scholar
  17. Chen H, Detmer SA, Ewald AJ et al (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200. doi: 10.1083/jcb.200211046 PubMedCentralPubMedGoogle Scholar
  18. Chen R, Valencia I, Zhong F et al (2004) Bcl-2 functionally interacts with inositol 1,4,5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1,4,5-trisphosphate. J Cell Biol 166:193–203. doi: 10.1083/jcb.200309146 PubMedCentralPubMedGoogle Scholar
  19. Chen Y, Sheng Z-H (2013) Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport. J Cell Biol 202:351–364. doi: 10.1083/jcb.201302040 PubMedCentralPubMedGoogle Scholar
  20. Cheng EHY, Sheiko TV, Fisher JK et al (2003) VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 301:513–517. doi: 10.1126/science.1083995 PubMedGoogle Scholar
  21. Copeland DE, Dalton AJ (1959) An association between mitochondria and the endoplasmic reticulum in cells of the pseudobranch gland of a teleost. J Biophys Biochem Cytol 5:393–396PubMedCentralPubMedGoogle Scholar
  22. Crompton M, Capano M, Carafoli E (1976) Respiration-dependent efflux of magnesium ions from heart mitochondria. Biochem J 154:735–742PubMedCentralPubMedGoogle Scholar
  23. Csordás G, Golenár T, Seifert EL et al (2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter. Cell Metab 17:976–987. doi: 10.1016/j.cmet.2013.04.020 PubMedCentralPubMedGoogle Scholar
  24. Das AM, Harris DA (1990) Control of mitochondrial ATP synthase in heart cells: inactive to active transitions caused by beating or positive inotropic agents. Cardiovasc Res 24:411–417PubMedGoogle Scholar
  25. De Brito OM, Scorrano L (2008) Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion. Antioxid Redox Signal 10:621–633. doi: 10.1089/ars.2007.1934 PubMedGoogle Scholar
  26. De Luca HF, Engstrom GW (1961) Calcium uptake by rat kidney mitochondria. Proc Natl Acad Sci U S A 47:1744–1750Google Scholar
  27. De Stefani D, Raffaello A, Teardo E et al (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336–340. doi: 10.1038/nature10230 PubMedGoogle Scholar
  28. Decker WK, Craigen WJ (2000) The tissue-specific, alternatively spliced single ATG exon of the type 3 voltage-dependent anion channel gene does not create a truncated protein isoform in vivo. Mol Genet Metab 70:69–74. doi: 10.1006/mgme.2000.2987 PubMedGoogle Scholar
  29. Denton RM, McCormack JG, Edgell NJ (1980) Role of calcium ions in the regulation of intramitochondrial metabolism. Effects of Na+, Mg2+ and ruthenium red on the Ca2+−stimulated oxidation of oxoglutarate and on pyruvate dehydrogenase activity in intact rat heart mitochondria. Biochem J 190:107–117PubMedCentralPubMedGoogle Scholar
  30. Dirnagl U, Lindauer U, Them A et al (1995) Global cerebral ischemia in the rat: online monitoring of oxygen free radical production using chemiluminescence in vivo. J Cereb Blood Flow Metab 15:929–940. doi: 10.1038/jcbfm.1995.118 PubMedGoogle Scholar
  31. Dong H, Wang S, Zhang Z et al (2013) The effect of mitochondrial calcium uniporter opener spermine on diazoxide against focal cerebral ischemia-reperfusion injury in rats. J Stroke Cerebrovasc Dis. doi: 10.1016/j.jstrokecerebrovasdis.2013.02.020 Google Scholar
  32. Eliseev RA, Filippov G, Velos J et al (2007) Role of cyclophilin D in the resistance of brain mitochondria to the permeability transition. Neurobiol Aging 28:1532–1542. doi: 10.1016/j.neurobiolaging.2006.06.022 PubMedGoogle Scholar
  33. Epand RF, Martinou J-C, Montessuit S et al (2002) Direct evidence for membrane pore formation by the apoptotic protein Bax. Biochem Biophys Res Commun 298:744–749PubMedGoogle Scholar
  34. Ferrer I, Friguls B, Dalfó E et al (2003) Caspase-dependent and caspase-independent signalling of apoptosis in the penumbra following middle cerebral artery occlusion in the adult rat. Neuropathol Appl Neurobiol 29:472–481. doi: 10.1046/j.0305-1846.2003.00485.x PubMedGoogle Scholar
  35. Gandhi S, Wood-Kaczmar A, Yao Z et al (2009) PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 33:627–638. doi: 10.1016/j.molcel.2009.02.013 PubMedCentralPubMedGoogle Scholar
  36. Gincel D, Vardi N, Shoshan-Barmatz V (2002) Retinal voltage-dependent anion channel: characterization and cellular localization. Invest Ophthalmol Vis Sci 43:2097–2104PubMedGoogle Scholar
  37. Giorgi C, De Stefani D, Bononi A et al (2009) Structural and functional link between the mitochondrial network and the endoplasmic reticulum. Int J Biochem Cell Biol 41:1817–1827. doi: 10.1016/j.biocel.2009.04.010 PubMedCentralPubMedGoogle Scholar
  38. Giorgi C, Ito K, Lin H-K et al (2010) PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330:1247–1251. doi: 10.1126/science.1189157 PubMedCentralPubMedGoogle Scholar
  39. Giorgio V, von Stockum S, Antoniel M et al (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci U S A 110:5887–5892. doi: 10.1073/pnas.1217823110 PubMedCentralPubMedGoogle Scholar
  40. Goyagi T, Goto S, Bhardwaj A et al (2001) Neuroprotective effect of sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is linked to reduced neuronal nitric oxide production. Stroke 32:1613–1620PubMedGoogle Scholar
  41. Hajnóczky G, Csordás G, Das S et al (2006) Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium 40:553–560. doi: 10.1016/j.ceca.2006.08.016 PubMedCentralPubMedGoogle Scholar
  42. Hansford RG, Zorov D (1998) Role of mitochondrial calcium transport in the control of substrate oxidation. Mol Cell Biochem 184:359–369PubMedGoogle Scholar
  43. Harukuni I, Bhardwaj A, Shaivitz AB et al (2000) σ1-Receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine affords neuroprotection from focal ischemia with prolonged reperfusion. Stroke 31:976–982. doi: 10.1161/01.STR.31.4.976 PubMedGoogle Scholar
  44. Hayashi T, Sasaki C, Iwai M et al (2001) Induction of PML immunoreactivity in rat brain neurons after transient middle cerebral artery occlusion. Neurol Res 23:772–776PubMedGoogle Scholar
  45. Hayashi T, Su T-P (2003) Sigma-1 receptors (sigma(1) binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export. J Pharmacol Exp Ther 306:718–725. doi: 10.1124/jpet.103.051284 PubMedGoogle Scholar
  46. Hayashi T, Su T-P (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131:596–610. doi: 10.1016/j.cell.2007.08.036 PubMedGoogle Scholar
  47. Hodge T, Colombini M (1997) Regulation of metabolite flux through voltage-gating of VDAC channels. J Membr Biol 157:271–279PubMedGoogle Scholar
  48. Huang H, Hu X, Eno CO et al (2013) An interaction between Bcl-xL and the voltage-dependent anion channel (VDAC) promotes mitochondrial Ca2+ uptake. J Biol Chem 288:19870–19881. doi: 10.1074/jbc.M112.448290 PubMedCentralPubMedGoogle Scholar
  49. Huckabee DB, Jekabsons MB (2011) Identification of Bax-voltage-dependent anion channel 1 complexes in digitonin-solubilized cerebellar granule neurons. J Neurochem 119:1137–1150. doi: 10.1111/j.1471-4159.2011.07499.x PubMedCentralPubMedGoogle Scholar
  50. Israelson A, Zaid H, Abu-Hamad S et al (2008) Mapping the ruthenium red-binding site of the voltage-dependent anion channel-1. Cell Calcium 43:196–204. doi: 10.1016/j.ceca.2007.05.006 PubMedGoogle Scholar
  51. Jonas EA (2009) Molecular participants in mitochondrial cell death channel formation during neuronal ischemia. Exp Neurol 218:203–212. doi: 10.1016/j.expneurol.2009.03.025 PubMedCentralPubMedGoogle Scholar
  52. Kann O, Schuchmann S, Buchheim K, Heinemann U (2003) Coupling of neuronal activity and mitochondrial metabolism as revealed by NAD(P)H fluorescence signals in organotypic hippocampal slice cultures of the rat. Neuroscience 119:87–100. doi: 10.1016/S0306-4522(03)00026-5 PubMedGoogle Scholar
  53. Kannurpatti SS, Biswal BB (2008) Mitochondrial Ca2+ uniporter blockers influence activation-induced CBF response in the rat somatosensory cortex. J Cereb Blood Flow Metab 28:772–785. doi: 10.1038/sj.jcbfm.9600574 PubMedGoogle Scholar
  54. Katnik C, Guerrero WR, Pennypacker KR et al (2006) Sigma-1 receptor activation prevents intracellular calcium dysregulation in cortical neurons during in vitro ischemia. J Pharmacol Exp Ther 319:1355–1365. doi: 10.1124/jpet.106.107557 PubMedGoogle Scholar
  55. Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364. doi: 10.1038/nature02246 PubMedGoogle Scholar
  56. Krajewski S, Krajewska M, Ellerby LM et al (1999) Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci U S A 96:5752–5757PubMedCentralPubMedGoogle Scholar
  57. Lee AC, Xu X, Colombini M (1996) The role of pyridine dinucleotides in regulating the permeability of the mitochondrial outer membrane. J Biol Chem 271:26724–26731. doi: 10.1074/jbc.271.43.26724 PubMedGoogle Scholar
  58. Lenzen S, Münster W, Rustenbeck I (1992) Dual effect of spermine on mitochondrial Ca2+ transport. Biochem J 286:597–602PubMedCentralPubMedGoogle Scholar
  59. Li Y, Lim S, Hoffman D et al (2009) HUMMR, a hypoxia- and HIF-1alpha-inducible protein, alters mitochondrial distribution and transport. J Cell Biol 185:1065–1081. doi: 10.1083/jcb.200811033 PubMedCentralPubMedGoogle Scholar
  60. Liu X, Hajnóczky G (2009) Ca2+−dependent regulation of mitochondrial dynamics by the Miro-Milton complex. Int J Biochem Cell Biol 41:1972–1976. doi: 10.1016/j.biocel.2009.05.013 PubMedCentralPubMedGoogle Scholar
  61. MacAskill AF, Rinholm JE, Twelvetrees AE et al (2009) Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron 61:541–555. doi: 10.1016/j.neuron.2009.01.030 PubMedCentralPubMedGoogle Scholar
  62. Mallilankaraman K, Cárdenas C, Doonan PJ et al (2012a) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14:1336–1343. doi: 10.1038/ncb2622 PubMedCentralPubMedGoogle Scholar
  63. Mallilankaraman K, Doonan P, Cárdenas C et al (2012b) MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival. Cell 151:630–644. doi: 10.1016/j.cell.2012.10.011 PubMedCentralPubMedGoogle Scholar
  64. Mannella CA, Marko M, Penczek P et al (1994) The internal compartmentation of rat-liver mitochondria: tomographic study using the high-voltage transmission electron microscope. Microsc Res Tech 27:278–283. doi: 10.1002/jemt.1070270403 PubMedGoogle Scholar
  65. Martin LJ, Adams NA, Pan Y et al (2011) The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation. J Neurosci 31:359–370. doi: 10.1523/JNEUROSCI.2225-10.2011 PubMedCentralPubMedGoogle Scholar
  66. Massa SM, Longo FM, Zuo J et al (1995) Cloning of rat grp75, an hsp70-family member, and its expression in normal and ischemic brain. J Neurosci Res 40:807–819. doi: 10.1002/jnr.490400612 PubMedGoogle Scholar
  67. Matlib MA, Zhou Z, Knight S et al (1998) Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+ uptake into mitochondria in vitro and in situ in single cardiac myocytes. J Biol Chem 273:10223–10231PubMedGoogle Scholar
  68. McCommis KS, Baines CP (2012) The role of VDAC in cell death: friend or foe? Biochim Biophys Acta 1818:1444–1450. doi: 10.1016/j.bbamem.2011.10.025 PubMedCentralPubMedGoogle Scholar
  69. Medler K, Gleason EL (2002) Mitochondrial Ca(2+) buffering regulates synaptic transmission between retinal amacrine cells. J Neurophysiol 87:1426–1439. doi: 10.1152/jn.00627.2001 PubMedGoogle Scholar
  70. Mekahli D, Bultynck G, Parys JB, De Smedt H, Missiaen L (2011) Endoplasmic-reticulum calcium depletion and disease. Cold Spring Harb Perspect Biol 3 pii:a004317. doi: 10.1101/cshperspect.a004317 Google Scholar
  71. Mendes CCP, Gomes DA, Thompson M et al (2005) The type III inositol 1,4,5-trisphosphate receptor preferentially transmits apoptotic Ca2+ signals into mitochondria. J Biol Chem 280:40892–40900. doi: 10.1074/jbc.M506623200 PubMedGoogle Scholar
  72. Mironov SL (2007) ADP regulates movements of mitochondria in neurons. Biophys J 92:2944–2952. doi: 10.1529/biophysj.106.092981 PubMedCentralPubMedGoogle Scholar
  73. Mironov SL, Symonchuk N (2006) ER vesicles and mitochondria move and communicate at synapses. J Cell Sci 119:4926–4934. doi: 10.1242/jcs.03254 PubMedGoogle Scholar
  74. Misko A, Jiang S, Wegorzewska I et al (2010) Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci 30:4232–4240. doi: 10.1523/JNEUROSCI.6248-09.2010 PubMedCentralPubMedGoogle Scholar
  75. Müller M, Mironov SL, Ivannikov MV et al (2005) Mitochondrial organization and motility probed by two-photon microscopy in cultured mouse brainstem neurons. Exp Cell Res 303:114–127. doi: 10.1016/j.yexcr.2004.09.025 PubMedGoogle Scholar
  76. Nagata E, Tanaka K, Gomi S et al (1994) Alteration of inositol 1,4,5-trisphosphate receptor after six-hour hemispheric ischemia in the gerbil brain. Neuroscience 61:983–990PubMedGoogle Scholar
  77. Oh KJ, Singh P, Lee K et al (2010) Conformational changes in BAK, a pore-forming proapoptotic Bcl-2 family member, upon membrane insertion and direct evidence for the existence of BH3-BH3 contact interface in BAK homo-oligomers. J Biol Chem 285:28924–28937. doi: 10.1074/jbc.M110.135293 PubMedCentralPubMedGoogle Scholar
  78. Oida Y, Izuta H, Oyagi A et al (2008) Induction of BiP, an ER-resident protein, prevents the neuronal death induced by transient forebrain ischemia in gerbil. Brain Res 1208:217–224. doi: 10.1016/j.brainres.2008.02.068 PubMedGoogle Scholar
  79. Ouyang Y-B, Xu L-J, Emery JF et al (2011) Overexpressing GRP78 influences Ca2+ handling and function of mitochondria in astrocytes after ischemia-like stress. Mitochondrion 11:279–286. doi: 10.1016/j.mito.2010.10.007 PubMedCentralPubMedGoogle Scholar
  80. Palty R, Ohana E, Hershfinkel M et al (2004) Lithium-calcium exchange is mediated by a distinct potassium-independent sodium-calcium exchanger. J Biol Chem 279:25234–25240. doi: 10.1074/jbc.M401229200 PubMedGoogle Scholar
  81. Palty R, Silverman WF, Hershfinkel M et al (2010) NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci U S A 107:436–441. doi: 10.1073/pnas.0908099107 PubMedCentralPubMedGoogle Scholar
  82. Pan X, Liu J, Nguyen T, Liu C, Sun J, Teng Y et al (2013) The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat Cell Biol 15:1464–1472. doi: 10.1038/ncb2868 PubMedGoogle Scholar
  83. Park E, Lee G-J, Choi S et al (2010) The role of glutamate release on voltage-dependent anion channels (VDAC)-mediated apoptosis in an eleven vessel occlusion model in rats. PLoS ONE 5:e15192. doi: 10.1371/journal.pone.0015192 PubMedCentralPubMedGoogle Scholar
  84. Parnis J, Montana V, Delgado-Martinez I et al (2013) Mitochondrial exchanger NCLX plays a major role in the intracellular Ca2+ signaling, gliotransmission, and proliferation of astrocytes. J Neurosci 33:7206–7219. doi: 10.1523/JNEUROSCI.5721-12.2013 PubMedGoogle Scholar
  85. Paschen W, Mengesdorf T (2005) Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease–therapeutic potential. Pharmacol Ther 108:362–375. doi: 10.1016/j.pharmthera.2005.05.008 PubMedGoogle Scholar
  86. Perocchi F, Gohil VM, Girgis HS et al (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature 467:291–296. doi: 10.1038/nature09358 PubMedCentralPubMedGoogle Scholar
  87. Petronilli V, Cola C, Bernardi P (1993) Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore. II. The minimal requirements for pore induction underscore a key role for transmembrane electrical potential, matrix pH, and matrix Ca2+. J Biol Chem 268:1011–1016PubMedGoogle Scholar
  88. Puka-Sundvall M, Gilland E, Hagberg H (2001) Cerebral hypoxia-ischemia in immature rats: involvement of mitochondrial permeability transition? Dev Neurosci 23:192–197PubMedGoogle Scholar
  89. Qiu J, Tan Y-W, Hagenston AM et al (2013) Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals. Nat Commun 4:2034. doi: 10.1038/ncomms3034 PubMedCentralPubMedGoogle Scholar
  90. Raghavan A, Sheiko T, Graham BH, Craigen WJ (2012) Voltage-dependant anion channels: novel insights into isoform function through genetic models. Biochim Biophys Acta 1818:1477–1485. doi: 10.1016/j.bbamem.2011.10.019 PubMedGoogle Scholar
  91. Rintoul GL, Filiano AJ, Brocard JB et al (2003) Glutamate decreases mitochondrial size and movement in primary forebrain neurons. J Neurosci 23:7881–7888PubMedGoogle Scholar
  92. Rizzuto R, Brini M, Murgia M, Pozzan T (1993) Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science 262:744–747PubMedGoogle Scholar
  93. Rizzuto R, Pozzan T (2006) Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 86:369–408. doi: 10.1152/physrev.00004.2005 PubMedGoogle Scholar
  94. Rong Y, Distelhorst CW (2008) Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Annu Rev Physiol 70:73–91. doi: 10.1146/annurev.physiol.70.021507.105852 PubMedGoogle Scholar
  95. Roy SS, Madesh M, Davies E et al (2009) Bad targets the permeability transition pore independent of Bax or Bak to switch between Ca2+−dependent cell survival and death. Mol Cell 33:377–388. doi: 10.1016/j.molcel.2009.01.018 PubMedCentralPubMedGoogle Scholar
  96. Ruscher K, Shamloo M, Rickhag M et al (2011) The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke. Brain 134:732–746. doi: 10.1093/brain/awq367 PubMedGoogle Scholar
  97. Sampson MJ, Lovell RS, Craigen WJ (1997) The murine voltage-dependent anion channel gene family. Conserved structure and function. J Biol Chem 272:18966–18973PubMedGoogle Scholar
  98. Sanganahalli BG, Herman P, Hyder F, Kannurpatti SS (2013) Mitochondrial calcium uptake capacity modulates neocortical excitability. J Cereb Blood Flow Metab 33:1115–1126. doi: 10.1038/jcbfm.2013.61 PubMedCentralPubMedGoogle Scholar
  99. Saotome M, Safiulina D, Szabadkai G et al (2008) Bidirectional Ca2+−dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci U S A 105:20728–20733. doi: 10.1073/pnas.0808953105 PubMedCentralPubMedGoogle Scholar
  100. Schendel SL, Xie Z, Montal MO et al (1997) Channel formation by antiapoptotic protein Bcl-2. Proc Natl Acad Sci U S A 94:5113–5118PubMedCentralPubMedGoogle Scholar
  101. Schinzel AC, Takeuchi O, Huang Z et al (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A 102:12005–12010. doi: 10.1073/pnas.0505294102 PubMedCentralPubMedGoogle Scholar
  102. Shimizu S, Matsuoka Y, Shinohara Y et al (2001) Essential role of voltage-dependent anion channel in various forms of apoptosis in mammalian cells. J Cell Biol 152:237–250PubMedCentralPubMedGoogle Scholar
  103. Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487. doi: 10.1038/20959 PubMedGoogle Scholar
  104. Solenski NJ, diPierro CG, Trimmer PA et al (2002) Ultrastructural changes of neuronal mitochondria after transient and permanent cerebral ischemia. Stroke 33:816–824. doi: 10.1161/hs0302.104541 PubMedGoogle Scholar
  105. Su T-P, Hayashi T, Maurice T et al (2010) The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci 31:557–566. doi: 10.1016/ PubMedCentralPubMedGoogle Scholar
  106. Szabadkai G, Bianchi K, Várnai P et al (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175:901–911. doi: 10.1083/jcb.200608073 PubMedCentralPubMedGoogle Scholar
  107. Trotman LC, Alimonti A, Scaglioni PP et al (2006) Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441:523–527. doi: 10.1038/nature04809 PubMedCentralPubMedGoogle Scholar
  108. Vance JE (1990) Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem 265:7248–7256PubMedGoogle Scholar
  109. Vaseva AV, Marchenko ND, Ji K et al (2012) p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149:1536–1548. doi: 10.1016/j.cell.2012.05.014 PubMedCentralPubMedGoogle Scholar
  110. Vasington FD, Murphy JV (1962) Ca ion uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation. J Biol Chem 237:2670–2677PubMedGoogle Scholar
  111. Wang X, Carlsson Y, Basso E et al (2009) Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury. J Neurosci 29:2588–2596. doi: 10.1523/JNEUROSCI.5832-08.2009 PubMedCentralPubMedGoogle Scholar
  112. Westphal D, Dewson G, Czabotar PE, Kluck RM (2011) Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta 1813:521–531. doi: 10.1016/j.bbamcr.2010.12.019 PubMedGoogle Scholar
  113. White C, Li C, Yang J et al (2005) The endoplasmic reticulum gateway to apoptosis by Bcl-X(L) modulation of the InsP3R. Nat Cell Biol 7:1021–1028. doi: 10.1038/ncb1302 PubMedCentralPubMedGoogle Scholar
  114. Xu L, Voloboueva LA, Ouyang Y et al (2009) Overexpression of mitochondrial Hsp70/Hsp75 in rat brain protects mitochondria, reduces oxidative stress, and protects from focal ischemia. J Cereb Blood Flow Metab 29:365–374. doi: 10.1038/jcbfm.2008.125 PubMedCentralPubMedGoogle Scholar
  115. Young KW, Bampton ETW, Pinòn L et al (2008) Mitochondrial Ca2+ signalling in hippocampal neurons. Cell Calcium 43:296–306. doi: 10.1016/j.ceca.2007.06.007 PubMedGoogle Scholar
  116. Yu Z, Liu N, Li Y et al (2013) Neuroglobin overexpression inhibits oxygen-glucose deprivation-induced mitochondrial permeability transition pore opening in primary cultured mouse cortical neurons. Neurobiol Dis 56:95–103. doi: 10.1016/j.nbd.2013.04.015 PubMedGoogle Scholar
  117. Zhang L, Gao X, Yuan X, Dong H, Zhang Z, Wang S (2013) Mitochondrial calcium uniporter opener spermine attenuates the cerebral protection of diazoxide through apoptosis in rats. J Stroke Cerebrovasc Dis pii:S1052-3057(13)00273-5. doi: 10.1016/j.jstrokecerebrovasdis.2013.07.007 Google Scholar
  118. Zhang SX, Zhang JP, Fletcher DL et al (1995) In situ hybridization of mRNA expression for IP3 receptor and IP3-3-kinase in rat brain after transient focal cerebral ischemia. Brain Res Mol Brain Res 32:252–260PubMedGoogle Scholar
  119. Zhao Q, Wang S, Li Y et al (2013) The role of the mitochondrial calcium uniporter in cerebral ischemia/reperfusion injury in rats involves regulation of mitochondrial energy metabolism. Mol Med Rep 7:1073–1080. doi: 10.3892/mmr.2013.1321 PubMedGoogle Scholar
  120. Zhao S, Yu Z, Zhao G et al (2012) Neuroglobin-overexpression reduces traumatic brain lesion size in mice. BMC Neurosci 13:67. doi: 10.1186/1471-2202-13-67 PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Michael K. E. Schäfer
    • 1
    • 3
  • Annika Pfeiffer
    • 2
  • Martin Jaeckel
    • 1
  • Alireza Pouya
    • 2
  • Amalia M. Dolga
    • 4
  • Axel Methner
    • 2
    • 3
  1. 1.Department of Anesthesiology, University Medical CenterJohannes Gutenberg University MainzMainzGermany
  2. 2.Department of Neurology, University Medical CenterJohannes Gutenberg University MainzMainzGermany
  3. 3.Focus Program Translational Neuroscience (FTN)Johannes Gutenberg University MainzMainzGermany
  4. 4.Institute of Pharmacology and Clinical PharmacyUniversity of MarburgMarburgGermany

Personalised recommendations