It is commonly believed that sustained elevations in the mitochondrial matrix Ca2+ concentration are a major feature of the intracellular cascade of lethal events during cerebral ischemia. The physical association between the endoplasmic reticulum (ER) and mitochondria, known as the mitochondria-associated ER membrane (MAM), enables highly efficient transmission of Ca2+ from the ER to mitochondria under both physiological and pathological conditions. Molecular chaperones are well known for their protective effects during cerebral ischemia. It has been demonstrated recently that many molecular chaperones coexist with MAM and regulate the MAM and thus Ca2+ concentration inside mitochondria. Here, we review recent research on cerebral ischemia and MAM, with a focus on molecular chaperones and ER-mitochondrial calcium transfer. 1. Introduction Stroke is one of the leading causes of death worldwide and a major cause of long-term disability [1]. Although many clinical trials have been completed in stroke patients, none of these have demonstrated protective efficacy except for thrombolysis [2, 3]. Suggested reasons for this failure include the complex interplay among multiple pathways (for review see [4–6]) including excitotoxicity, mitochondrial dysfunction, acidotoxicity, ionic imbalance, oxidative stress, and inflammation, which can all lead to cell death and irreversible tissue injury. A generally accepted cell death pathway after cerebral ischemia is mitochondrial permeability transition (MPT) pore opening (Figure 1(a)). Ischemia leads to energy deprivation and loss of ion homeostasis. As the cells are unable to maintain a negative membrane potential, they depolarize, leading to the opening of voltage-gated calcium channels and release of excitatory amino acids into the extracellular space [7]. This cascade of events leads to a massive entry of calcium and this increase in free cytosolic calcium is transmitted to the matrix of mitochondria by Ca2+ channels and exchangers located on the inner mitochondrial membrane. Recently ER stress was found to be one of the effects of excitotoxicity, that is, exposure to toxic levels of excitatory neurotransmitters, with release of Ca2+ from the ER via both ryanodine receptors and IP3R, with release from inositol trisphosphate receptors (IP3Rs) leading to mitochondrial Ca2+ overload and activation of apoptosis [8]. Excessive increases in matrix Ca2+ alter the permeability of mitochondria and finally open the MPT pore [9], causing the release of cytochrome c [10] and other proapoptotic factors into the cytoplasm. The
References
[1]
D. Lloyd-Jones, R. J. Adams, T. M. Brown et al., “Executive summary: heart disease and stroke statistics-2010 update: a report from the american heart association,” Circulation, vol. 121, no. 7, pp. e46–e215, 2010.
[2]
J. O. Blakeley and R. H. Llinas, “Thrombolytic therapy for acute ischemic stroke,” Journal of the Neurological Sciences, vol. 261, no. 1-2, pp. 55–62, 2007.
[3]
V. J. Marder, R. Jahan, T. Gruber, A. Goyal, and V. Arora, “Thrombolysis with plasmin: implications for stroke treatment,” Stroke, vol. 41, no. 10, pp. S45–S49, 2010.
[4]
B. K. Siesjo, E. Elmer, S. Janelidze et al., “Role and mechanisms of secondary mitochondrial failure,” Acta Neurochirurgica, Supplement, vol. 1999, supplement 73, pp. 7–13, 1999.
[5]
B. K. Siesjo, Y. B. Ouyang, T. Kristian, et al., “Role of mitochondria in immediate and delayed reperfusion damage,” in Maturation Phenomenon in Cerebral Ischemia III, U. Ito, Ed., Springer Verlag, Berlin, Germany, 1999.
[6]
Y. B. Ouyang, T. Kristian, P. A. Li, and B. K. Siesjo, “Mitochondria, free radicals, and ischemic brain damage,” in Pharmacology of Cerebral Ischemia, J. Krieglstein, Ed., Wissenschaftliche Verlagsgesellschaft, Stuttgart, Germany, 1998.
[7]
T. Kristián, Y. Ouyang, and B. K. Siesj？, “Calcium-induced neuronal cell death in vivo and in vitro: are the pathophysiologic mechanisms different?” Advances in Neurology, vol. 71, pp. 107–118, 1996.
[8]
A. Ruiz, C. Matute, and E. Alberdi, “Endoplasmic reticulum Ca2+ release through ryanodine and IP3 receptors contributes to neuronal excitotoxicity,” Cell Calcium, vol. 46, no. 4, pp. 273–281, 2009.
[9]
Y. B. Ouyang, S. Kuroda, T. Kristián, and B. K. Siesj？, “Release of mitochondrial aspartate aminotransferase (mAST) following transient focal cerebral ischemia suggests the opening of a mitochondrial permeability transition pore,” Neuroscience Research Communications, vol. 20, no. 3, pp. 167–173, 1997.
[10]
Y.-B. Ouyang, Y. Tan, M. Comb et al., “Survival- and death-promoting events after transient cerebral ischemia(colon): phosphorylation of Akt, release of cytochrome C, and activation of caspase- like proteases,” Journal of Cerebral Blood Flow and Metabolism, vol. 19, no. 10, pp. 1126–1135, 1999.
[11]
Y. Gouriou, N. Demaurex, P. Bijlenga, and U. de Marchi, “Mitochondrial calcium handling during ischemia-induced cell death in neurons,” Biochimie, vol. 93, no. 12, pp. 2060–2067, 2011.
[12]
Y. Kirichok, G. Krapivinsky, and D. E. Clapham, “The mitochondrial calcium uniporter is a highly selective ion channel,” Nature, vol. 427, no. 6972, pp. 360–364, 2004.
[13]
D. G. Nicholls and S. L. Budd, “Mitochondria and neuronal survival,” Physiological Reviews, vol. 80, no. 1, pp. 315–360, 2000.
[14]
P. Bernardi, “Mitochondrial transport of cations: channels, exchangers, and permeability transition,” Physiological Reviews, vol. 79, no. 4, pp. 1127–1155, 1999.
[15]
R. Rizzuto and T. Pozzan, “Microdomains of intracellular Ca2+: molecular determinants and functional consequences,” Physiological Reviews, vol. 86, no. 1, pp. 369–408, 2006.
[16]
R. Rizzuto, M. Brini, M. Murgia, and T. Pozzan, “Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria,” Science, vol. 262, no. 5134, pp. 744–747, 1993.
[17]
R. Rizzuto, P. Pinton, W. Carrington et al., “Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses,” Science, vol. 280, no. 5370, pp. 1763–1766, 1998.
[18]
T. Hayashi, R. Rizzuto, G. Hajnoczky, and T. P. Su, “MAM: more than just a housekeeper,” Trends in Cell Biology, vol. 19, no. 2, pp. 81–88, 2009.
[19]
Y.-B. Ouyang, Y. Lu, S. Yue et al., “MiR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo,” Neurobiology of Disease, vol. 45, no. 1, pp. 555–563, 2012.
[20]
G. X. Wang, G. R. Li, Y. D. Wang, T. S. Yang, and Y. B. Ouyang, “Characterization of neuronal cell death in normal and diabetic rats following exprimental focal cerebral ischemia,” Life Sciences, vol. 69, no. 23, pp. 2801–2810, 2001.
[21]
Y. B. Ouyang, L. A. Voloboueva, L. J. Xu, and R. G. Giffard, “Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia,” Journal of Neuroscience, vol. 27, no. 16, pp. 4253–4260, 2007.
[22]
Y. B. Ouyang, L. J. Xu, J. F. Emery, A. S. Lee, and R. G. Giffard, “Overexpressing GRP78 influences Ca2+ handling and function of mitochondria in astrocytes after ischemia-like stress,” Mitochondrion, 2010.
[23]
Y. B. Ouyang, L. J. Xu, Y. J. Sun, and R. G. Giffard, “Overexpression of inducible heat shock protein 70 and its mutants in astrocytes is associated with maintenance of mitochondrial physiology during glucose deprivation stress,” Cell Stress and Chaperones, vol. 11, no. 2, Article ID csac. 2006.CSC-182R, pp. 180–186, 2006.
[24]
Y. B. Ouyang, S. G. Carriedo, and R. G. Giffard, “Effect of Bcl-xL overexpression on reactive oxygen species, intracellular calcium, and mitochondrial membrane potential following injury in astrocytes,” Free Radical Biology and Medicine, vol. 33, no. 4, pp. 544–551, 2002.
[25]
Y. B. Ouyang and R. G. Giffard, “Bcl-xL maintains mitochondrial function in murine astrocytes deprived of glucose,” Journal of Cerebral Blood Flow and Metabolism, vol. 23, no. 3, pp. 275–279, 2003.
[26]
Y. B. Ouyang, L. Xu, and R. G. Giffard, “Geldanamycin treatment reduces delayed CA1 damage in mouse hippocampal organotypic cultures subjected to oxygen glucose deprivation,” Neuroscience Letters, vol. 380, no. 3, pp. 229–233, 2005.
[27]
B. Hoehn, T. M. Ringer, L. Xu et al., “Overexpression of HSP72 after induction of experimental stroke protects neurons from ischemic damage,” Journal of Cerebral Blood Flow and Metabolism, vol. 21, no. 11, pp. 1303–1309, 2001.
[28]
T. Kudo, S. Kanemoto, H. Hara et al., “A molecular chaperone inducer protects neurons from ER stress,” Cell Death and Differentiation, vol. 15, no. 2, pp. 364–375, 2008.
[29]
Y. Oida, H. Izuta, A. Oyagi et al., “Induction of BiP, an ER-resident protein, prevents the neuronal death induced by transient forebrain ischemia in gerbil,” Brain Research C, vol. 1208, pp. 217–224, 2008.
[30]
S. Rajdev, K. Hara, Y. Kokubo et al., “Mice overexpressing rat heat shock protein 70 are protected against cerebral infarction,” Annals of Neurology, vol. 47, no. 6, pp. 782–791, 2000.
[31]
L. Xu, L. A. Voloboueva, Y. Ouyang, J. F. Emery, and R. G. Giffard, “Overexpression of mitochondrial Hsp70/Hsp75 in rat brain protects mitochondria, reduces oxidative stress, and protects from focal ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 2, pp. 365–374, 2009.
[32]
L. Xu, X. Xiong, Y. Ouyang, G. Barreto, and R. Giffard, “Heat shock protein 72 (Hsp72) improves long term recovery after focal cerebral ischemia in mice,” Neuroscience Letters, vol. 488, no. 3, pp. 279–282, 2011.
[33]
H. Kinouchi, F. R. Sharp, M. P. Hill, J. Koistinaho, S. M. Sagar, and P. H. Chan, “Induction of 70-kDa heat shock protein and hsp70 mRNA following transient focal cerebral ischemia in the rat,” Journal of Cerebral Blood Flow and Metabolism, vol. 13, no. 1, pp. 105–115, 1993.
[34]
H. Kinouchi, F. R. Sharp, J. Koistinaho, K. Hicks, H. Kamii, and P. H. Chan, “Induction of heat shock hsp70 mRNA and HSP70 kDa protein in neurons in the “penumbra” following focal cerebral ischemia in the rat,” Brain Research, vol. 619, no. 1-2, pp. 334–338, 1993.
[35]
K. Vass, W. J. Welch, and T. S. Nowak, “Localization of 70-kDa stress protein induction in gerbil brain after ischemia,” Acta Neuropathologica, vol. 77, no. 2, pp. 128–135, 1988.
[36]
S. M. Massa, F. M. Longo, J. Zuo, S. Wang, J. Chen, and F. R. Sharp, “Cloning of rat grp75, an hsp70-family member, and its expression in normal and ischemic brain,” Journal of Neuroscience Research, vol. 40, no. 6, pp. 807–819, 1995.
[37]
A. L. Barabási and Z. N. Oltvai, “Network biology: understanding the cell's functional organization,” Nature Reviews Genetics, vol. 5, no. 2, pp. 101–113, 2004.
[38]
P. Csermely, “Strong links are important, but weak links stabilize them,” Trends in Biochemical Sciences, vol. 29, no. 7, pp. 331–334, 2004.
[39]
C. Soti, C. Pál, B. Papp, and P. Csermely, “Molecular chaperones as regulatory elements of cellular networks,” Current Opinion in Cell Biology, vol. 17, no. 2, pp. 210–215, 2005.
[40]
P. Csermely and L. Vigh, Eds., Molecular Aspects of the Stress Reponse: Chaperones, Membranes and Networks, Springer Science, New York, NY, USA, 2007.
[41]
M. Ni, Y. Zhang, and A. S. Lee, “Beyond the endoplasmic reticulum: a typical GRP78 in cell viability, signalling and therapeutic targeting,” Biochemical Journal, vol. 434, no. 2, pp. 181–188, 2011.
[42]
T. Panaretakis, O. Kepp, U. Brockmeier et al., “Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death,” EMBO Journal, vol. 28, no. 5, pp. 578–590, 2009.
[43]
R. Tufi, T. Panaretakis, K. Bianchi et al., “Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin,” Cell Death and Differentiation, vol. 15, no. 2, pp. 274–282, 2008.
[44]
K. T. Pfaffenbach and A. S. Lee, “The critical role of GRP78 in physiologic and pathologic stress,” Current Opinion in Cell Biology, 2010.
[45]
M. Wang, S. Wey, Y. Zhang, R. Ye, and A. S. Lee, “Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders,” Antioxidants and Redox Signaling, vol. 11, no. 9, pp. 2307–2316, 2009.
[46]
M. Gonzalez-Gronow, M. A. Selim, J. Papalas, and S. V. Pizzo, “GRP78: a multifunctional receptor on the cell surface,” Antioxidants and Redox Signaling, vol. 11, no. 9, pp. 2299–2306, 2009.
[47]
L. H. Zhang, X. L. Yang, X. Zhang, J. X. Cheng, and W. Zhang, “Association of elevated GRP78 expression with increased astrocytoma malignancy via Akt and ERK pathways,” Brain Research, 2010.
[48]
R. G. Giffard, R. Q. Han, J. F. Emery, M. Duan, and J. F. Pittet, “Regulation of apoptotic and inflammatory cell signaling in cerebral ischemia: the complex roles of heat shock protein 70,” Anesthesiology, vol. 109, no. 2, pp. 339–348, 2008.
[49]
D. E. Copeland and A. J. Dalton, “An association between mitochondria and the endoplasmic reticulum in cells of the pseudobranch gland of a teleost,” The Journal of biophysical and biochemical cytology, vol. 5, no. 3, pp. 393–396, 1959.
[50]
J. R. Ruby, R. F. Dyer, and R. G. Skalko, “Continuities between mitochondria and endoplasmic reticulum in the mammalian ovary,” Zeitschrift für Zellforschung und Mikroskopische Anatomie, vol. 97, no. 1, pp. 30–37, 1969.
[51]
C. A. Mannella, M. Marko, P. Penczek, D. Barnard, and J. Frank, “The internal compartmentation of rat-liver mitochondria: tomographic study using the high-voltage transmission electron microscope,” Microscopy Research and Technique, vol. 27, no. 4, pp. 278–283, 1994.
[52]
B. J. Soltys and R. S. Gupta, “Interrelationships of endoplasmic reticulum, mitochondria, intermediate filaments, and microtubules—a quadruple fluorescence labeling study,” Biochemistry and Cell Biology, vol. 70, no. 10-11, pp. 1174–1186, 1992.
[53]
O. Camici and L. Corazzi, “Phosphatidylserine translocation into brain mitochondria: involvement of a fusogenic protein associated with mitochondrial membranes,” Molecular and Cellular Biochemistry, vol. 175, no. 1-2, pp. 71–80, 1997.
[54]
J. E. Vance, “Phospholipid synthesis in a membrane fraction associated with mitochondria,” Journal of Biological Chemistry, vol. 265, no. 13, pp. 7248–7256, 1990.
[55]
G. Csordás, C. Renken, P. Várnai et al., “Structural and functional features and significance of the physical linkage between ER and mitochondria,” Journal of Cell Biology, vol. 174, no. 7, pp. 915–921, 2006.
[56]
R. Bravo, J. M. Vicencio, V. Parra et al., “Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress,” Journal of Cell Science, vol. 124, no. 13, pp. 2143–2152, 2011.
[57]
M. Chami, B. Oulès, G. Szabadkai, R. Tacine, R. Rizzuto, and P. Paterlini-Bréchot, “Role of SERCA1 Truncated Isoform in the Proapoptotic Calcium Transfer from ER to Mitochondria during ER Stress,” Molecular Cell, vol. 32, no. 5, pp. 641–651, 2008.
[58]
C. Giorgi, D. de Stefani, A. Bononi, R. Rizzuto, and P. Pinton, “Structural and functional link between the mitochondrial network and the endoplasmic reticulum,” International Journal of Biochemistry and Cell Biology, vol. 41, no. 10, pp. 1817–1827, 2009.
[59]
M. Lebiedzinska, G. Szabadkai, A. W. E. Jones, J. Duszynski, and M. R. Wieckowski, “Interactions between the endoplasmic reticulum, mitochondria, plasma membrane and other subcellular organelles,” International Journal of Biochemistry and Cell Biology, vol. 41, no. 10, pp. 1805–1816, 2009.
[60]
G. Szabadkai, K. Bianchi, P. Várnai et al., “Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels,” Journal of Cell Biology, vol. 175, no. 6, pp. 901–911, 2006.
[61]
T. Hayashi and T. P. Su, “Regulating ankyrin dynamics: roles of sigma-1 receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 2, pp. 491–496, 2001.
[62]
T. Hayashi and T. P. Su, “Sigma-1 receptor chaperones at the ER- mitochondrion interface regulate Ca2+ signaling and cell survival,” Cell, vol. 131, no. 3, pp. 596–610, 2007.
[63]
T. P. Su, T. Hayashi, T. Maurice, S. Buch, and A. E. Ruoho, “The sigma-1 receptor chaperone as an inter-organelle signaling modulator,” Trends in Pharmacological Sciences, vol. 31, no. 12, pp. 557–566, 2010.
[64]
Z. Wu and W. D. Bowen, “Role of sigma-1 receptor C-terminal segment in inositol 1,4,5-trisphosphate receptor activation: constitutive enhancement of calcium signaling in MCF-7 tumor cells,” Journal of Biological Chemistry, vol. 283, no. 42, pp. 28198–28215, 2008.
[65]
T. Higo, M. Hattori, T. Nakamura, T. Natsume, T. Michikawa, and K. Mikoshiba, “Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44,” Cell, vol. 120, no. 1, pp. 85–98, 2005.
[66]
L. M. John, J. D. Lechleiter, and P. Camacho, “Differential modulation of SERCA2 isoforms by calreticulin,” Journal of Cell Biology, vol. 142, no. 4, pp. 963–973, 1998.
[67]
H. L. Roderick, J. D. Lechleiter, and P. Camacho, “Cytosolic phosphorylation of calnexin controls intracellular Ca2+ oscillations via an interaction with SERCA2b,” Journal of Cell Biology, vol. 149, no. 6, pp. 1235–1247, 2000.
[68]
T. Simmen, J. E. Aslan, A. D. Blagoveshchenskaya et al., “PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis,” EMBO Journal, vol. 24, no. 4, pp. 717–729, 2005.
[69]
M. R. Wieckowski, G. Szabadkai, M. Wasilewski, P. Pinton, J. Duszyński, and R. Rizzuto, “Overexpression of adenine nucleotide translocase reduces Ca2+ signal transmission between the ER and mitochondria,” Biochemical and Biophysical Research Communications, vol. 348, no. 2, pp. 393–399, 2006.
[70]
O. M. de Brito and L. Scorrano, “Mitofusin 2 tethers endoplasmic reticulum to mitochondria,” Nature, vol. 456, no. 7222, pp. 605–610, 2008.
[71]
M. R. M. R. Wieckowski, C. Giorgi, M. Lebiedzinska, J. Duszynski, and P. Pinton, “Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells,” Nature Protocols, vol. 4, no. 11, pp. 1582–1590, 2009.
[72]
D. de Stefani, A. Raffaello, E. Teardo, I. Szabó, and R. Rizzuto, “A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter,” Nature, vol. 476, no. 7360, pp. 336–340, 2011.
[73]
E. Rapizzi, P. Pinton, G. Szabadkai et al., “Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria,” Journal of Cell Biology, vol. 159, no. 4, pp. 613–624, 2002.
[74]
C. Cárdenas, R. A. Miller, I. Smith et al., “Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria,” Cell, vol. 142, no. 2, pp. 270–283, 2010.
[75]
M. H？yer-Hansen, L. Bastholm, P. Szyniarowski et al., “Control of Macroautophagy by Calcium, Calmodulin-Dependent Kinase Kinase-β, and Bcl-2,” Molecular Cell, vol. 25, no. 2, pp. 193–205, 2007.
[76]
J. M. Vicencio, C. Ortiz, A. Criollo et al., “The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1,” Cell Death and Differentiation, vol. 16, no. 7, pp. 1006–1017, 2009.
[77]
J. M. Vicencio, S. Lavandero, and G. Szabadkai, “Ca2+, autophagy and protein degradation: thrown off balance in neurodegenerative disease,” Cell Calcium, vol. 47, no. 2, pp. 112–121, 2010.
[78]
A. Deniaud, O. Sharaf El Dein, E. Maillier et al., “Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis,” Oncogene, vol. 27, no. 3, pp. 285–299, 2008.
[79]
S. Marchi, A. Rimessi, C. Giorgi et al., “Akt kinase reducing endoplasmic reticulum Ca2+ release protects cells from Ca2+-dependent apoptotic stimuli,” Biochemical and Biophysical Research Communications, vol. 375, no. 4, pp. 501–505, 2008.
[80]
R. Rizzuto, S. Marchi, M. Bonora et al., “Ca2+ transfer from the ER to mitochondria: when, how and why,” Biochimica et Biophysica Acta, vol. 1787, no. 11, pp. 1342–1351, 2009.
[81]
L. Scorrano, S. A. Oakes, J. T. Opferman et al., “BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis,” Science, vol. 300, no. 5616, pp. 135–139, 2003.
[82]
T. Szado, V. Vanderheyden, J. B. Parys et al., “Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 7, pp. 2427–2432, 2008.
[83]
L. A. Voloboueva, M. Duan, Y. Ouyang, J. F. Emery, C. Stoy, and R. G. Giffard, “Overexpression of mitochondrial Hsp70/Hsp75 protects astrocytes against ischemic injury in vitro,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 5, pp. 1009–1016, 2008.
[84]
J. A. Fishback, M. J. Robson, Y. T. Xu, and R. R. Matsumoto, “Sigma receptors: potential targets for a new class of antidepressant drug,” Pharmacology and Therapeutics, vol. 127, no. 3, pp. 271–282, 2010.
[85]
D. Fontanilla, M. Johannessen, A. R. Hajipour, N. V. Cozzi, M. B. Jackson, and A. E. Ruoho, “The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator,” Science, vol. 323, no. 5916, pp. 934–937, 2009.
[86]
T. Maurice and T. P. Su, “The pharmacology of sigma-1 receptors,” Pharmacology and Therapeutics, vol. 124, no. 2, pp. 195–206, 2009.
[87]
F. C. Sun, S. Wei, C. W. Li, Y. S. Chang, C. C. Chao, and Y. K. Lai, “Localization of GRP78 to mitochondria under the unfolded protein response,” Biochemical Journal, vol. 396, no. 1, pp. 31–39, 2006.
[88]
J. M. Baughman, F. Perocchi, H. S. Girgis et al., “Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter,” Nature, vol. 476, no. 7360, pp. 341–345, 2011.
[89]
F. Perocchi, V. M. Gohil, H. S. Girgis et al., “MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake,” Nature, vol. 467, no. 7313, pp. 291–296, 2010.
