Neurotoxicity Research

, Volume 35, Issue 1, pp 1–18 | Cite as

Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and Enhance Complex I Activity in Physiological Condition but Protect Against Pathological Oxidative Stress

  • Nino Goguadze
  • Elene Zhuravliova
  • Didier Morin
  • Davit Mikeladze
  • Tangui MauriceEmail author


The sigma1 receptor (σ1R) is a chaperone protein residing at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), where it modulates Ca2+ exchange between the ER and mitochondria by interacting with inositol-1,4,5 trisphosphate receptors (IP3Rs). The σ1R is highly expressed in the central nervous system and its activation stimulates neuromodulation and neuroprotection, for instance in Alzheimer’s disease (AD) models in vitro and in vivo. σ1R effects on mitochondria pathophysiology and the downstream signaling are still not fully understood. We here evaluated the impacts of σ1R ligands in mouse mitochondria preparations on reactive oxygen species (ROS) production, mitochondrial respiration, and complex activities, in physiological condition and after direct application of amyloid Aβ1–42 peptide. σ1R agonists (2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate hydrochloride (PRE-084), tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine (ANAVEX1-41, AN1-41), (S)-1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one (ANAVEX3-71, AN3-71), dehydroepiandrosterone-3 sulfate (DHEA), donepezil) increased mitochondrial ROS in a σ1R antagonist-sensitive manner but decreased Aβ1–42-induced increase in ROS. σ1R ligands (agonists or antagonists) did not impact respiration but attenuated Aβ1–42-induced alteration. σ1R agonists (PRE-084, AN1-41, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73, AN2-73), AN3-71) increased complex I activity, in a Ca2+-dependent and σ1R antagonist-sensitive manner. σ1R ligands failed to affect complex II, III, and IV activities. The increase in complex I activity explain the σ1R-induced increase in ROS since ligands failed to affect other sources of ROS accumulation in mitochondria and homogenates, namely NADPH oxidase (NOX) and superoxide dismutase (SOD) activities. Furthermore, Aβ1–42 significantly decreased the activity of complexes I and IV and σ1R agonists attenuated the Aβ1–42-induced complex I and IV dysfunctions. σ1R activity in mitochondria therefore results in a Ying-Yang effect, by triggering moderate ROS increase acting as a physiological signal and promoting a marked anti-oxidant effect in pathological (Aβ) conditions.


Sigma-1 receptor Mitochondria Oxidative stress Amyloid toxicity 



The present work is a collaboration between INSERM UMR-S1198, University of Montpellier (France), and the Institute of Chemical Biology, Ilia State University (Tbilisi, Georgia). Nino Goguadze thanks the Euroeast exchange program for PhD students. We thank Melissa Soriano, Laura Tairi, Lucie Crouzier, and Marie-Christine Lebars for technical help.

Compliance with Ethical Standards

Conflict of Interest

This study was supported in part by Anavex Life Sciences (New York, USA). The company had no role in the study design, analyses of the data, and preparation of the manuscript. All authors declare no conflict of interest related to the present work.


  1. Angelova PR, Abramov AY (2016) Functional role of mitochondrial reactive oxygen species in physiology. Free Radic Biol Med 100:81–85. CrossRefPubMedGoogle Scholar
  2. Angelova PR, Abramov AY (2017) Alpha-synuclein and β-amyloid—different targets, same players: calcium, free radicals and mitochondria in the mechanism of neurodegeneration. Biochem Biophys Res Commun 483:1110–1115. CrossRefPubMedGoogle Scholar
  3. Area-Gomez E, de Groof AJ, Boldogh I, Bird TD, Gibson GE, Koehler CM, Yu WH, Duff KE, Yaffe MP, Pon LA, Schon EA (2009) Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol 175:1810–1816. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Atamna H, Frey WH II (2007) Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease. Mitochondrion 7:297–310.
  5. Berridge MJ (1993) Cell signalling. A tale of two messengers. Nature 365:388–389CrossRefGoogle Scholar
  6. Brailoiu GC, Deliu E, Console-Bram LM, Soboloff J, Abood ME, Unterwald EM, Brailoiu E (2016) Cocaine inhibits store-operated Ca2+ entry in brain microvascular endothelial cells: critical role for sigma-1 receptors. Biochem J 473:1–5. CrossRefPubMedGoogle Scholar
  7. Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH (2011) Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Hum Mol Genet 20:4515–4529. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chaki S, Tanaka M, Muramatsu M, Otomo S (1994) NE-100, a novel potent sigma ligand, preferentially binds to sigma1 binding sites in guinea pig brain. Eur J Pharmacol 251:R1–R2CrossRefGoogle Scholar
  9. Chaturvedi RK, Beal MF (2013) Mitochondria targeted therapeutic approaches in Parkinson's and Huntington's diseases. Mol Cell Neurosci 55:101–114. CrossRefPubMedGoogle Scholar
  10. Collins RO, Thomas RC (2001) The effect of calcium pump inhibitors on the response of intracellular calcium to caffeine in snail neurones. Cell Calcium 30:41–48CrossRefGoogle Scholar
  11. Csordás G, Renken C, Várnai P, Walter L, Weaver D, Buttle KF, Balla T, Mannella CA, Hajnóczky G (2006) Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol 174:915–921. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Csordás G, Várnai P, Golenár T, Roy S, Purkins G, Schneider TG, Balla T, Hajnóczky G (2010) Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell 39:121–132. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Fisher A, Bezprozvanny I, Wu L, Ryskamp DA, Bar-Ner N, Natan N, Brandeis R, Elkon H, Nahum V, Gershonov E, LaFerla FM, Medeiros R (2016) AF710B, a novel M1/σ1 agonist with therapeutic efficacy in animal models of Alzheimer’s disease. Neurodegener Dis 16:95–110. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Francardo V, Bez F, Wieloch T, Nissbrandt H, Ruscher K, Cenci MA (2014) Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism. Brain 137:1998–2014. CrossRefPubMedGoogle Scholar
  15. Gamou S, Shimizu N (1995) Hydrogen peroxide preferentially enhances the tyrosine phosphorylation of epidermal growth factor receptor. FEBS Lett 357:161–164CrossRefGoogle Scholar
  16. Giachin G, Bouverot R, Acajjaoui S, Pantalone S, Soler-López M (2016) Dynamics of human mitochondrial complex I assembly: implications for neurodegenerative diseases. Front Mol Biosci 3:43. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Glancy B, Balaban RS (2012) Role of mitochondrial Ca2+ in the regulation of cellular energetics. Biochemistry 51:2959–2973. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hayashi T, Maurice T, Su TP (2000) Ca2+ signaling via sigma1-receptors: novel regulatory mechanism affecting intracellular Ca2+ concentration. J Pharmacol Exp Ther 293:788–798PubMedGoogle Scholar
  19. Hayashi T, Rizzuto R, Hajnoczky G, Su TP (2009) MAM: more than just a housekeeper. Trends Cell Biol 19:81–88. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131:596–610. CrossRefPubMedGoogle Scholar
  21. Hernandez-Zimbron LF, Luna-Muñoz J, Mena R, Vazquez-Ramirez R, Kubli-Garfias C, Cribbs DH, Manoutcharian K, Gevorkian G (2012) Amyloid-β peptide binds to cytochrome C oxidase subunit 1. PLoS One 7:e42344. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hildeman DA, Mitchell T, Aronow B, Wojciechowski S, Kappler J, Marrack P (2003) Control of Bcl-2 expression by reactive oxygen species. Proc Natl Acad Sci U S A 100:15035–15040CrossRefGoogle Scholar
  23. Honrath B, Matschke L, Meyer T, Magerhans L, Perocchi F, Ganjam GK, Zischka H, Krasel C, Gerding A, Bakker BM, Bünemann M, Strack S, Decher N, Culmsee C, Dolga AM (2017) SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake. Cell Death Differ 24:761–773. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hroudová J, Singh N, Fišar Z (2014) Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer's disease. Biomed Res Int 2014:175062. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Hyrskyluoto A, Pulli I, Törnqvist K, Huu Ho T, Korhonen L, Lindholm D (2013) Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involvement of calpastatin and the NF-κB pathway. Cell Death Dis 4:e646. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Johnston PA (2011) Redox cycling compounds generate H2O2 in HTS buffers containing strong reducing reagents—real hits or promiscuous artifacts? Curr Opin Chem Biol 15:174–182. CrossRefPubMedGoogle Scholar
  27. Kato K, Hayako H, Ishihara Y, Marui S, Iwane M, Miyamoto M (1999) TAK-147, an acetylcholinesterase inhibitor, increases choline acetyltransferase activity in cultured rat septal cholinergic neurons. Neurosci Lett 260:5–8CrossRefGoogle Scholar
  28. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. J Pharmacol Pharmacother 1:94–99. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Ko LW, Sheu KF, Thaler HT, Markesbery WR, Blass JP (2001) Selective loss of KGDHC-enriched neurons in Alzheimer temporal cortex: does mitochondrial variation contribute to selective vulnerability? J Mol Neurosci 17:361–369CrossRefGoogle Scholar
  30. Kowall NW, McKee AC, Yankner BA, Beal MF (1992) In vivo neurotoxicity of β-amyloid [β1-40] and the β25-35 fragment. Neurobiol Aging 13:537–542CrossRefGoogle Scholar
  31. Lahmy V, Long R, Morin D, Villard V, Maurice T (2015) Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer's disease model. Front Cell Neurosci 8:463. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Lahmy V, Meunier J, Malmström S, Naert G, Givalois L, Kim SH, Villard V, Vamvakides A, Maurice T (2013) Blockade of Tau hyperphosphorylation and Aβ1-42 generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and σ1 receptor agonist, in a nontransgenic mouse model of Alzheimer's disease. Neuropsychopharmacology 38:1706–1723. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Leal NS, Schreiner B, Pinho CM, Filadi R, Wiehager B, Karlström H, Pizzo P, Ankarcrona M (2016) Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production. J Cell Mol Med 20:1686–1695. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Li D, Ueta E, Kimura T, Yamamoto T, Osaki T (2004) Reactive oxygen species (ROS) control the expression of Bcl-2 family proteins by regulating their phosphorylation and ubiquitination. Cancer Sci 95:644–650CrossRefGoogle Scholar
  35. Malouf AT (1992) Effect of β amyloid peptides on neurons in hippocampal slice cultures. Neurobiol Aging 13:543–551CrossRefGoogle Scholar
  36. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH (2006) Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15:1437–1449. CrossRefPubMedGoogle Scholar
  37. Marrazzo A, Caraci F, Salinaro ET, Su TP, Copani A, Ronsisvalle G (2005) Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity. Neuroreport 16:1223–1226CrossRefGoogle Scholar
  38. Martina M, Turcotte ME, Halman S, Bergeron R (2007) The sigma-1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels in rat hippocampus. J Physiol 578:143–157. CrossRefPubMedGoogle Scholar
  39. Mastrogiacoma F, Lindsay JG, Bettendorff L, Rice J, Kish SJ (1996) Brain protein and alpha-ketoglutarate dehydrogenase complex activity in Alzheimer’s disease. Ann Neurol 39:592–598CrossRefGoogle Scholar
  40. Mastrogiacomo F, Bergeron C, Kish SJ (1993) Brain a-ketoglutarate dehydrogenase complex activity in Alzheimer’s disease. J Neurochem 61:2007–2014CrossRefGoogle Scholar
  41. Maurice T, Goguadze N (2017) Sigma-1 (σ1) receptor in memory and neurodegenerative diseases. Handb Exp Pharmacol 2017; in press.
  42. Maurice T, Su T (2009) The pharmacology of sigma-1 receptors. Pharmacol Ther 124:195–206. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Maurice T, Lockhart BP, Privat A (1996) Amnesia induced in mice by centrally administered β-amyloid peptides involves cholinergic dysfunction. Brain Res 706:181–193CrossRefGoogle Scholar
  44. Maurice T, Urani A, Phan VL, Romieu P (2001) The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities. Brain Res Rev 37:116–132CrossRefGoogle Scholar
  45. Meunier J, Hayashi T (2010) Sigma-1 receptors regulate Bcl-2 expression by reactive oxygen species-dependent transcriptional regulation of nuclear factor KB. J Pharmacol Exp Ther 332:388–397. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Meunier J, Ieni J, Maurice T (2006) The anti-amnesic and neuroprotective effects of donepezil against amyloid β25-35 peptide-induced toxicity in mice involve an interaction with the σ1 receptor. Br J Pharmacol 149: 998–1012.
  47. Miller CC, Hale P, Pentland AP (1994) Ultraviolet B injury increases prostaglandin synthesis through a tyrosine kinase-dependent pathway. Evidence for UVB-induced epidermal growth factor receptor activation. J Biol Chem 269:3529–3533PubMedGoogle Scholar
  48. Monnet FP, Mahé V, Robel P, Baulieu EE (1995) Neurosteroids, via sigma receptors, modulate the [3H]norepinephrine release evoked by N-methyl-D-aspartate in the rat hippocampus. Proc Natl Acad Sci U S A 92:3774–3778CrossRefGoogle Scholar
  49. Natsvlishvili N, Goguadze N, Zhuravliova E, Mikeladze D (2015) Sigma-1 receptor directly interacts with Rac1-GTPase in the brain mitochondria. BMC Biochem 16:11. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767CrossRefGoogle Scholar
  51. Parks JK, Smith TS, Trimmer PA, Bennett JP Jr, Parker WD Jr (2001) Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. J Neurochem 76:1050–1056CrossRefGoogle Scholar
  52. Praticò D, Uryu K, Leight S, Trojanoswki JQ, Lee VM (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21:4183–4187CrossRefGoogle Scholar
  53. Pugazhenthi S, Nesterova A, Jambal P, Audesirk G, Kern M, Cabell L, Eves E, Rosner MR, Boxer LM, Reusch JE (2003) Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal neurons. J Neurochem 84:982–996CrossRefGoogle Scholar
  54. Rigoulet M, Yoboue ED, Devin A (2011) Mitochondrial ROS generation and its regulation: mechanisms involved in H2O2 signaling. Antioxid Redox Signal 14:459–468. CrossRefPubMedGoogle Scholar
  55. Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13:566–578. CrossRefPubMedGoogle Scholar
  56. Rusiñol AE, Cui Z, Chen MH, Vance JE (1994) A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins. J Biol Chem 269:27494–27502PubMedGoogle Scholar
  57. Sah P (1996) Ca2+-activated K+ currents in neurones: types, physiological roles and modulation. Trends Neurosci 19:150–154CrossRefGoogle Scholar
  58. Schreiner B, Hedskog L, Wiehager B, Ankarcrona M (2015) Amyloid-β peptides are generated in mitochondria-associated endoplasmic reticulum membranes. J Alzheimers Dis 43:369–374. CrossRefPubMedGoogle Scholar
  59. Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases. Nat Cell Biol 6:1054–1061CrossRefGoogle Scholar
  60. Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Molec Cell 48:158–167. CrossRefPubMedGoogle Scholar
  61. Shah MM, Haylett DG (2002) K+ currents generated by NMDA receptor activation in rat hippocampal pyramidal neurons. J Neurophysiol 87:2983–2989CrossRefGoogle Scholar
  62. Sohur US, Dixit MN, Chen CL, Byrom MW, Kerr LA (1999) Rel/NF-κB represses bcl-2 transcription in pro-B lymphocytes. Gene Expr 8:219–229PubMedGoogle Scholar
  63. Srivastava S (2016) Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders. Clin Transl Med 5:25. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Stone SJ, Vance JE (2000) Phosphatidylserine synthase-1 and -2 are localized to mitochondria-associated membranes. J Biol Chem 275:34534–34540CrossRefGoogle Scholar
  65. Stram AR, Payne RM (2016) Post-translational modifications in mitochondria: protein signaling in the powerhouse. Cell Mol Life Sci 73:4063–4073. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Su TP, London ED, Jaffe JH (1988) Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science 240:219–221CrossRefGoogle Scholar
  67. Su TP, Hayashi T, Maurice T, Buch S, Ruoho AE (2010) The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci 31:557–566. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Su TP, Su TC, Nakamura Y, Tsai SY (2016) The sigma-1 receptor as a pluripotent modulator in living systems. Trends Pharmacol Sci 37:262–278CrossRefGoogle Scholar
  69. Szabadkai G, Simoni AM, Bianchi K, De Stefani D, Leo S, Wieckowski MR, Rizzuto R (2006) Mitochondrial dynamics and Ca2+ signaling. Biochim Biophys Acta 1763:442–449. CrossRefPubMedGoogle Scholar
  70. Tahara EB, Navarete FD, Kowaltowski AJ (2009) Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation. Free Radic Biol Med 2009 46:1283–1297. CrossRefGoogle Scholar
  71. Tsai SY, Hayashi T, Harvey BK, Wang Y, Wu WW, Shen RF, Zhang Y, Becker KG, Hoffer BJ, Su TP (2009) Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1xGTP pathway. Proc Natl Acad Sci U S A 106:22468–22473. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Tsukada H, Nishiyama S, Ohba H, Kanazawa M, Kakiuchi T, Harada N (2014) Comparing amyloid-β deposition, neuroinflammation, glucose metabolism, and mitochondrial complex I activity in brain: a PET study in aged monkeys. Eur J Nucl Med Mol Imaging 41:2127–2136. CrossRefPubMedGoogle Scholar
  73. van Rossum GS, Drummen GP, Verkleij AJ, Post JA, Boonstra J (2004) Activation of cytosolic phospholipase A2 in Her14 fibroblasts by hydrogen peroxide: a p42/44(MAPK)-dependent and phosphorylation-independent mechanism. Biochim Biophys Acta 1636:183–195CrossRefGoogle Scholar
  74. Villard V, Espallergues J, Keller E, Alkam T, Nitta A, Yamada K, Nabeshima T, Vamvakides A, Maurice T (2009) Antiamnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid β25-35-induced toxicity in mice. Neuropsychopharmacology 34:1552–1566. CrossRefPubMedGoogle Scholar
  75. Villard V, Espallergues J, Keller E, Vamvakides A, Maurice T (2011) Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma11) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative. J Psychopharmacol 25:1101–1117. CrossRefPubMedGoogle Scholar
  76. Willems PH, Valsecchi F, Distelmaier F, Verkaart S, Visch HJ, Smeitink JA, Koopman WJ (2008) Mitochondrial Ca2+ homeostasis in human NADH:ubiquinone oxidoreductase deficiency. Cell Calcium 44:123–133. CrossRefPubMedGoogle Scholar
  77. Zhang D, Zhang Y, Liu G, Zhang J (2006) Dactylorhin B reduces toxic effects of β-amyloid fragment (25-35) on neuron cells and isolated rat brain mitochondria. Naunyn Schmiedeberg's Arch Pharmacol 374:117–125CrossRefGoogle Scholar
  78. Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ (2000) Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 192:1001–1014CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.MMDN, Université Montpellier, EPHE, INSERM, UMR-S1198Montpellier cedex 5France
  2. 2.Institute of Chemical BiologyIlia State UniversityTbilisiGeorgia
  3. 3.INSERM, UMR-S955, UPEC, Faculty of MedicineUniversité Paris-EstCréteilFrance

Personalised recommendations