Sex Differences in Ischemia/Reperfusion Injury: The Role of Mitochondrial Permeability Transition

  • Jasmine A. Fels
  • Giovanni ManfrediEmail author
Original Paper


Brain and heart ischemia are among the leading causes of death and disability in both men and women, but there are significant sex differences in the incidence and severity of these diseases. Ca2+ dysregulation in response to ischemia/reperfusion injury (I/RI) is a well-recognized pathogenic mechanism leading to the death of affected cells. Excess intracellular Ca2+ causes mitochondrial matrix Ca2+ overload that can result in mitochondrial permeability transition (MPT), which can have severe consequences for mitochondrial function and trigger cell death. Recent findings indicate that estrogens and their related receptors are involved in the regulation of MPT, suggesting that sex differences in I/RI could be linked to estrogen-dependent modulation of mitochondrial Ca2+. Here, we review the evidence supporting sex differences in I/RI and the role of estrogen and estrogen receptors in producing these differences, the involvement of mitochondrial Ca2+ overload in disease pathogenesis, and the estrogen-dependent modulation of MPT that may contribute to sex differences.


Ischemia Sex Mitochondrial permeability transition Calcium Estrogen Estrogen receptor 



This work was supported by NIH/NINDS Grant No. 1R01NS095692.


  1. 1.
    Ostadal B, Ostadal P (2014) Sex-based differences in cardiac ischaemic injury and protection: therapeutic implications. Br J Pharmacol 171:541–554CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Gibson CL, Attwood L (2016) The impact of gender on stroke pathology and treatment. Neurosci Biobehav Rev 67:119–124CrossRefPubMedGoogle Scholar
  3. 3.
    Spychala MS, Honarpisheh P, McCullough LD (2017) Sex differences in neuroinflammation and neuroprotection in ischemic stroke. J Neurosci Res 95:462–471CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Herson PS, Palmateer J, Hurn PD (2013) Biological sex and mechanisms of ischemic brain injury. Transl Stroke Res 4:413–419CrossRefPubMedGoogle Scholar
  5. 5.
    Haast RA, Gustafson DR, Kiliaan AJ (2012) Sex differences in stroke. J Cereb Blood Flow Metab 32:2100–2107CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ahnstedt H, McCullough LD, Cipolla MJ (2016) The importance of considering sex differences in translational stroke research. Transl Stroke Res 7:261–273CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Gibson CL (2013) Cerebral ischemic stroke: is gender important? J Cereb Blood Flow Metab 33:1355–1361CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Chauhan A, Moser H, McCullough LD (2017) Sex differences in ischaemic stroke: potential cellular mechanisms. Clin Sci (Lond) 131:533–552CrossRefGoogle Scholar
  9. 9.
    Girijala RL, Sohrabji F, Bush RL (2017) Sex differences in stroke: review of current knowledge and evidence. Vasc Med 22:135–145CrossRefPubMedGoogle Scholar
  10. 10.
    Appelros P, Stegmayr B, Terent A (2009) Sex differences in stroke epidemiology: a systematic review. Stroke 40:1082–1090CrossRefPubMedGoogle Scholar
  11. 11.
    Di Carlo A, Lamassa M, Baldereschi M, Pracucci G, Basile AM, Wolfe CD, Giroud M, Rudd A, Ghetti A, Inzitari D, European BSoSCG (2003) Sex differences in the clinical presentation, resource use, and 3-month outcome of acute stroke in Europe: data from a multicenter multinational hospital-based registry. Stroke 34:1114–1119CrossRefPubMedGoogle Scholar
  12. 12.
    Dodson JA, Arnold SV, Reid KJ, Gill TM, Rich MW, Masoudi FA, Spertus JA, Krumholz HM, Alexander KP (2012) Physical function and independence 1 year after myocardial infarction: observations from the translational research investigating underlying disparities in recovery from acute myocardial infarction: patients’ health status registry. Am Heart J 163:790–796CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Humphries KH, Izadnegahdar M, Sedlak T, Saw J, Johnston N, Schenck-Gustafsson K, Shah RU, Regitz-Zagrosek V, Grewal J, Vaccarino V, Wei J, Bairey Merz CN (2017) Sex differences in cardiovascular disease—impact on care and outcomes. Front Neuroendocrinol 46:46–70CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhu C, Xu F, Wang X, Shibata M, Uchiyama Y, Blomgren K, Hagberg H (2006) Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia. J Neurochem 96:1016–1027CrossRefPubMedGoogle Scholar
  15. 15.
    Hurn PD, Vannucci SJ, Hagberg H (2005) Adult or perinatal brain injury: does sex matter? Stroke 36:193–195CrossRefPubMedGoogle Scholar
  16. 16.
    DiNapoli VA, Huber JD, Houser K, Li X, Rosen CL (2008) Early disruptions of the blood-brain barrier may contribute to exacerbated neuronal damage and prolonged functional recovery following stroke in aged rats. Neurobiol Aging 29:753–764CrossRefPubMedGoogle Scholar
  17. 17.
    Johnson MS, Moore RL, Brown DA (2006) Sex differences in myocardial infarct size are abolished by sarcolemmal KATP channel blockade in rat. Am J Physiol Heart Circ Physiol 290:H2644–H2647CrossRefPubMedGoogle Scholar
  18. 18.
    Booth EA, Lucchesi BR (2008) Estrogen-mediated protection in myocardial ischemia-reperfusion injury. Cardiovasc Toxicol 8:101–113CrossRefPubMedGoogle Scholar
  19. 19.
    Rocca WA, Grossardt BR, Miller VM, Shuster LT, Brown RD Jr (2012) Premature menopause or early menopause and risk of ischemic stroke. Menopause 19:272–277CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lisabeth LD, Beiser AS, Brown DL, Murabito JM, Kelly-Hayes M, Wolf PA (2009) Age at natural menopause and risk of ischemic stroke: the Framingham heart study. Stroke 40:1044–1049CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Harman SM, Naftolin F, Brinton EA, Judelson DR (2005) Is the estrogen controversy over? deconstructing the women’s health initiative study: a critical evaluation of the evidence. Ann N Y Acad Sci 1052:43–56CrossRefPubMedGoogle Scholar
  22. 22.
    Simpkins JW, Rajakumar G, Zhang YQ, Simpkins CE, Greenwald D, Yu CJ, Bodor N, Day AL (1997) Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. J Neurosurg 87:724–730CrossRefPubMedGoogle Scholar
  23. 23.
    Carswell HV, Dominiczak AF, Macrae IM (2000) Estrogen status affects sensitivity to focal cerebral ischemia in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 278:H290–H294CrossRefPubMedGoogle Scholar
  24. 24.
    Suzuki S, Brown CM, Wise PM (2009) Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 30:201–211CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ross JL, Howlett SE (2012) Age and ovariectomy abolish beneficial effects of female sex on rat ventricular myocytes exposed to simulated ischemia and reperfusion. PLoS ONE 7:e38425CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hale SL, Birnbaum Y, Kloner RA (1997) Estradiol, administered acutely, protects ischemic myocardium in both female and male rabbits. J Cardiovasc Pharmacol Ther 2:47–52CrossRefPubMedGoogle Scholar
  27. 27.
    Miller NR, Jover T, Cohen HW, Zukin RS, Etgen AM (2005) Estrogen can act via estrogen receptor alpha and beta to protect hippocampal neurons against global ischemia-induced cell death. Endocrinology 146:3070–3079CrossRefPubMedGoogle Scholar
  28. 28.
    Booth EA, Marchesi M, Kilbourne EJ, Lucchesi BR (2003) 17Beta-estradiol as a receptor-mediated cardioprotective agent. J Pharmacol Exp Ther 307:395–401CrossRefPubMedGoogle Scholar
  29. 29.
    Bopassa JC, Eghbali M, Toro L, Stefani E (2010) A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 298:H16–H23CrossRefPubMedGoogle Scholar
  30. 30.
    Kabir ME, Singh H, Lu R, Olde B, Leeb-Lundberg LM, Bopassa JC (2015) G protein-coupled estrogen receptor 1 mediates acute estrogen-induced cardioprotection via MEK/ERK/GSK-3beta pathway after ischemia/reperfusion. PLoS ONE 10:e0135988CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Choi DW (1985) Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 58:293–297CrossRefPubMedGoogle Scholar
  32. 32.
    Brewer GJ, Reichensperger JD, Brinton RD (2006) Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons. Neurobiol Aging 27:306–317CrossRefPubMedGoogle Scholar
  33. 33.
    Burstein SR, Kim HJ, Fels JA, Qian L, Zhang S, Zhou P, Starkov AA, Iadecola C, Manfredi G (2018) Estrogen receptor beta modulates permeability transition in brain mitochondria. Biochim Biophys Acta Bioenerg 1859:423–433CrossRefPubMedGoogle Scholar
  34. 34.
    Mendelowitsch A, Ritz MF, Ros J, Langemann H, Gratzl O (2001) 17beta-estradiol reduces cortical lesion size in the glutamate excitotoxicity model by enhancing extracellular lactate: a new neuroprotective pathway. Brain Res 901:230–236CrossRefPubMedGoogle Scholar
  35. 35.
    Zhao L, Brinton RD (2007) Estrogen receptor alpha and beta differentially regulate intracellular Ca(2+) dynamics leading to ERK phosphorylation and estrogen neuroprotection in hippocampal neurons. Brain Res 1172:48–59CrossRefPubMedGoogle Scholar
  36. 36.
    Yang SH, Sarkar SN, Liu R, Perez EJ, Wang X, Wen Y, Yan LJ, Simpkins JW (2009) Estrogen receptor beta as a mitochondrial vulnerability factor. J Biol Chem 284:9540–9548CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Jovanovic S, Jovanovic A, Shen WK, Terzic A (2000) Low concentrations of 17beta-estradiol protect single cardiac cells against metabolic stress-induced Ca2+ loading. J Am Coll Cardiol 36:948–952CrossRefPubMedGoogle Scholar
  38. 38.
    Tymianski M, Charlton MP, Carlen PL, Tator CH (1993) Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci 13:2085–2104CrossRefPubMedGoogle Scholar
  39. 39.
    Peng TI, Greenamyre JT (1998) Privileged access to mitochondria of calcium influx through N-methyl-D-aspartate receptors. Mol Pharmacol 53:974–980PubMedGoogle Scholar
  40. 40.
    Cross JL, Meloni BP, Bakker AJ, Lee S, Knuckey NW (2010) Modes of neuronal calcium entry and homeostasis following cerebral ischemia. Stroke Res Treat 2010:316862PubMedPubMedCentralGoogle Scholar
  41. 41.
    Garcia-Dorado D, Ruiz-Meana M, Inserte J, Rodriguez-Sinovas A, Piper HM (2012) Calcium-mediated cell death during myocardial reperfusion. Cardiovasc Res 94:168–180CrossRefPubMedGoogle Scholar
  42. 42.
    Nayler WG (1981) The role of calcium in the ischemic myocardium. Am J Pathol 102:262–270PubMedPubMedCentralGoogle Scholar
  43. 43.
    Chiong M, Wang ZV, Pedrozo Z, Cao DJ, Troncoso R, Ibacache M, Criollo A, Nemchenko A, Hill JA, Lavandero S (2011) Cardiomyocyte death: mechanisms and translational implications. Cell Death Dis 2:e244CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Pallafacchina G, Zanin S, Rizzuto R (2018) Recent advances in the molecular mechanism of mitochondrial calcium uptake. F1000Research. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Bernardi P, von Stockum S (2012) The permeability transition pore as a Ca(2+) release channel: new answers to an old question. Cell Calcium 52:22–27CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Duchen MR (2012) Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflugers Arch 464:111–121CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Gouriou Y, Demaurex N, Bijlenga P, De Marchi U (2011) Mitochondrial calcium handling during ischemia-induced cell death in neurons. Biochimie 93:2060–2067CrossRefPubMedGoogle Scholar
  48. 48.
    Stout AK, Raphael HM, Kanterewicz BI, Klann E, Reynolds IJ (1998) Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci 1:366–373CrossRefPubMedGoogle Scholar
  49. 49.
    Castilho RF, Hansson O, Ward MW, Budd SL, Nicholls DG (1998) Mitochondrial control of acute glutamate excitotoxicity in cultured cerebellar granule cells. J Neurosci 18:10277–10286CrossRefPubMedGoogle Scholar
  50. 50.
    Vergun O, Keelan J, Khodorov BI, Duchen MR (1999) Glutamate-induced mitochondrial depolarisation and perturbation of calcium homeostasis in cultured rat hippocampal neurones. J Physiol 519(2):451–466CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Hunter DR, Haworth RA (1979) The Ca2+-induced membrane transition in mitochondria: III. Transitional Ca2+ release. Arch Biochem Biophys 195:468–477CrossRefPubMedGoogle Scholar
  52. 52.
    Szabo I, Zoratti M (1992) The mitochondrial megachannel is the permeability transition pore. J Bioenerg Biomembr 24:111–117CrossRefPubMedGoogle Scholar
  53. 53.
    Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341(2):233–249CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Halestrap AP, Richardson AP (2015) The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J Mol Cell Cardiol 78:129–141CrossRefPubMedGoogle Scholar
  55. 55.
    Petronilli V, Penzo D, Scorrano L, Bernardi P, Di Lisa F (2001) The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J Biol Chem 276:12030–12034CrossRefPubMedGoogle Scholar
  56. 56.
    Giorgio V, Guo L, Bassot C, Petronilli V, Bernardi P (2018) Calcium and regulation of the mitochondrial permeability transition. Cell Calcium 70:56–63CrossRefPubMedGoogle Scholar
  57. 57.
    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
  58. 58.
    Doczi J, Turiak L, Vajda S, Mandi M, Torocsik B, Gerencser AA, Kiss G, Konrad C, Adam-Vizi V, Chinopoulos C (2011) Complex contribution of cyclophilin D to Ca2+-induced permeability transition in brain mitochondria, with relation to the bioenergetic state. J Biol Chem 286:6345–6353CrossRefPubMedGoogle Scholar
  59. 59.
    Zoratti M, Szabo I (1995) The mitochondrial permeability transition. Biochim Biophys Acta 1241:139–176CrossRefPubMedGoogle Scholar
  60. 60.
    Crompton M, Virji S, Ward JM (1998) Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. Eur J Biochem 258:729–735CrossRefPubMedGoogle Scholar
  61. 61.
    Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Doczi J, Torocsik B, Echaniz-Laguna A, Mousson de Camaret B, Starkov A, Starkova N, Gal A, Molnar MJ, Kawamata H, Manfredi G, Adam-Vizi V, Chinopoulos C (2016) Alterations in voltage-sensing of the mitochondrial permeability transition pore in ANT1-deficient cells. Sci Rep 6:26700CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Alavian KN, Beutner G, Lazrove E, Sacchetti S, Park HA, Licznerski P, Li H, Nabili P, Hockensmith K, Graham M, Porter GA Jr, Jonas EA (2014) An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci USA 111:10580–10585CrossRefPubMedGoogle Scholar
  64. 64.
    Bonora M, Morganti C, Morciano G, Pedriali G, Lebiedzinska-Arciszewska M, Aquila G, Giorgi C, Rizzo P, Campo G, Ferrari R, Kroemer G, Wieckowski MR, Galluzzi L, Pinton P (2017) Mitochondrial permeability transition involves dissociation of F1FO ATP synthase dimers and C-ring conformation. EMBO Rep 18:1077–1089CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Zhou W, Marinelli F, Nief C, Faraldo-Gomez JD (2017) Atomistic simulations indicate the c-subunit ring of the F1Fo ATP synthase is not the mitochondrial permeability transition pore. Elife 6:e23781CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabo I, Lippe G, Bernardi P (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA 110:5887–5892CrossRefPubMedGoogle Scholar
  67. 67.
    Bernardi P, Di Lisa F, Fogolari F, Lippe G (2015) From ATP to PTP and back: a dual function for the mitochondrial ATP synthase. Circ Res 116:1850–1862CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    He J, Ford HC, Carroll J, Ding S, Fearnley IM, Walker JE (2017) Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase. Proc Natl Acad Sci USA 114:3409–3414CrossRefPubMedGoogle Scholar
  69. 69.
    He J, Carroll J, Ding S, Fearnley IM, Walker JE (2017) Permeability transition in human mitochondria persists in the absence of peripheral stalk subunits of ATP synthase. Proc Natl Acad Sci USA 114:9086–9091CrossRefPubMedGoogle Scholar
  70. 70.
    Giorgio V, Soriano ME, Basso E, Bisetto E, Lippe G, Forte MA, Bernardi P (2010) Cyclophilin D in mitochondrial pathophysiology. Biochim Biophys Acta 1797:1113–1118CrossRefPubMedGoogle Scholar
  71. 71.
    Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, Hetz C, Danial NN, Moskowitz MA, Korsmeyer SJ (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci USA 102:12005–12010CrossRefPubMedGoogle Scholar
  72. 72.
    Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P (2005) Properties of the permeability transition pore in mitochondria devoid of cyclophilin D. J Biol Chem 280:18558–18561CrossRefPubMedGoogle Scholar
  73. 73.
    Izzo V, Bravo-San Pedro JM, Sica V, Kroemer G, Galluzzi L (2016) Mitochondrial permeability transition: new findings and persisting uncertainties. Trends Cell Biol 26:655–667CrossRefPubMedGoogle Scholar
  74. 74.
    Crompton M, Ellinger H, Costi A (1988) Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem J 255:357–360PubMedPubMedCentralGoogle Scholar
  75. 75.
    Hansson MJ, Morota S, Chen L, Matsuyama N, Suzuki Y, Nakajima S, Tanoue T, Omi A, Shibasaki F, Shimazu M, Ikeda Y, Uchino H, Elmer E (2011) Cyclophilin D-sensitive mitochondrial permeability transition in adult human brain and liver mitochondria. J Neurotrauma 28:143–153CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Diaz-Ruiz A, Vergara P, Perez-Severiano F, Segovia J, Guizar-Sahagun G, Ibarra A, Rios C (2005) Cyclosporin-A inhibits constitutive nitric oxide synthase activity and neuronal and endothelial nitric oxide synthase expressions after spinal cord injury in rats. Neurochem Res 30:245–251CrossRefPubMedGoogle Scholar
  77. 77.
    Gauba E, Guo L, Du H (2017) Cyclophilin D promotes brain mitochondrial F1FO ATP synthase dysfunction in aging mice. J Alzheimers Dis 55:1351–1362CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Giorgio V, Bisetto E, Soriano ME, Dabbeni-Sala F, Basso E, Petronilli V, Forte MA, Bernardi P, Lippe G (2009) Cyclophilin D modulates mitochondrial F0F1-ATP synthase by interacting with the lateral stalk of the complex. J Biol Chem 284:33982–33988CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Chinopoulos C, Konrad C, Kiss G, Metelkin E, Torocsik B, Zhang SF, Starkov AA (2011) Modulation of F0F1-ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels. FEBS J 278:1112–1125CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Beck SJ, Guo L, Phensy A, Tian J, Wang L, Tandon N, Gauba E, Lu L, Pascual JM, Kroener S, Du H (2016) Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer’s disease. Nat Commun 7:11483CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Bernardi P, Petronilli V (1996) The permeability transition pore as a mitochondrial calcium release channel: a critical appraisal. J Bioenerg Biomembr 28:131–138CrossRefPubMedGoogle Scholar
  82. 82.
    Ichas F, Jouaville LS, Mazat JP (1997) Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89:1145–1153CrossRefPubMedGoogle Scholar
  83. 83.
    Ichas F, Mazat JP (1998) From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state. Biochim Biophys Acta 1366:33–50CrossRefPubMedGoogle Scholar
  84. 84.
    Huser J, Blatter LA (1999) Fluctuations in mitochondrial membrane potential caused by repetitive gating of the permeability transition pore. Biochem J 343(2):311–317CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Wang W, Fang H, Groom L, Cheng A, Zhang W, Liu J, Wang X, Li K, Han P, Zheng M, Yin J, Wang W, Mattson MP, Kao JP, Lakatta EG, Sheu SS, Ouyang K, Chen J, Dirksen RT, Cheng H (2008) Superoxide flashes in single mitochondria. Cell 134:279–290CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Agarwal A, Wu PH, Hughes EG, Fukaya M, Tischfield MA, Langseth AJ, Wirtz D, Bergles DE (2017) Transient opening of the mitochondrial permeability transition pore induces microdomain calcium transients in astrocyte processes. Neuron 93:587–605 (e587)CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Korge P, Yang L, Yang JH, Wang Y, Qu Z, Weiss JN (2011) Protective role of transient pore openings in calcium handling by cardiac mitochondria. J Biol Chem 286:34851–34857CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Altschuld RA, Hohl CM, Castillo LC, Garleb AA, Starling RC, Brierley GP (1992) Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes. Am J Physiol 262:H1699–H1704PubMedGoogle Scholar
  89. 89.
    De Marchi E, Bonora M, Giorgi C, Pinton P (2014) The mitochondrial permeability transition pore is a dispensable element for mitochondrial calcium efflux. Cell Calcium 56:1–13CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, Herman B (1998) The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1366:177–196CrossRefPubMedGoogle Scholar
  91. 91.
    Brown MR, Sullivan PG, Geddes JW (2006) Synaptic mitochondria are more susceptible to Ca2+ overload than nonsynaptic mitochondria. J Biol Chem 281:11658–11668CrossRefPubMedGoogle Scholar
  92. 92.
    Naga KK, Sullivan PG, Geddes JW (2007) High cyclophilin D content of synaptic mitochondria results in increased vulnerability to permeability transition. J Neurosci 27:7469–7475CrossRefPubMedGoogle Scholar
  93. 93.
    Porter GA Jr, Beutner G (2018) Cyclophilin D, somehow a master regulator of mitochondrial function. Biomolecules 8:176CrossRefPubMedCentralGoogle Scholar
  94. 94.
    Lemasters JJ, Theruvath TP, Zhong Z, Nieminen AL (2009) Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta 1787:1395–1401CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Rasola A, Bernardi P (2007) The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis 12:815–833CrossRefPubMedGoogle Scholar
  96. 96.
    Starkov AA, Chinopoulos C, Fiskum G (2004) Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury. Cell Calcium 36:257–264CrossRefPubMedGoogle Scholar
  97. 97.
    Shiga Y, Onodera H, Matsuo Y, Kogure K (1992) Cyclosporin A protects against ischemia-reperfusion injury in the brain. Brain Res 595:145–148CrossRefPubMedGoogle Scholar
  98. 98.
    Uchino H, Elmer E, Uchino K, Lindvall O, Siesjo BK (1995) Cyclosporin A dramatically ameliorates CA1 hippocampal damage following transient forebrain ischaemia in the rat. Acta Physiol Scand 155:469–471CrossRefPubMedGoogle Scholar
  99. 99.
    Argaud L, Gateau-Roesch O, Muntean D, Chalabreysse L, Loufouat J, Robert D, Ovize M (2005) Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol 38:367–374CrossRefPubMedGoogle Scholar
  100. 100.
    Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434:652–658CrossRefPubMedGoogle Scholar
  101. 101.
    Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662CrossRefPubMedGoogle Scholar
  102. 102.
    Tsujimoto Y, Shimizu S (2007) Role of the mitochondrial membrane permeability transition in cell death. Apoptosis 12:835–840CrossRefPubMedGoogle Scholar
  103. 103.
    Simpkins JW, Dykens JA (2008) Mitochondrial mechanisms of estrogen neuroprotection. Brain Res Rev 57:421–430CrossRefPubMedGoogle Scholar
  104. 104.
    Lobaton CD, Vay L, Hernandez-Sanmiguel E, Santodomingo J, Moreno A, Montero M, Alvarez J (2005) Modulation of mitochondrial Ca(2+) uptake by estrogen receptor agonists and antagonists. Br J Pharmacol 145:862–871CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Horvat A, Petrovic S, Nedeljkovic N, Martinovic JV, Nikezic G (2000) Estradiol affect Na-dependent Ca2+ efflux from synaptosomal mitochondria. Gen Physiol Biophys 19:59–71PubMedGoogle Scholar
  106. 106.
    Nilsen J, Diaz Brinton R (2003) Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial calcium and Bcl-2 expression. Proc Natl Acad Sci USA 100:2842–2847CrossRefPubMedGoogle Scholar
  107. 107.
    Kim HJ, Magrane J, Starkov AA, Manfredi G (2012) The mitochondrial calcium regulator cyclophilin D is an essential component of oestrogen-mediated neuroprotection in amyotrophic lateral sclerosis. Brain 135:2865–2874CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Ribeiro RF Jr, Ronconi KS, Morra EA, Do Val Lima PR, Porto ML, Vassallo DV, Figueiredo SG, Stefanon I (2016) Sex differences in the regulation of spatially distinct cardiac mitochondrial subpopulations. Mol Cell Biochem 419:41–51CrossRefPubMedGoogle Scholar
  109. 109.
    Milerova M, Drahota Z, Chytilova A, Tauchmannova K, Houstek J, Ostadal B (2016) Sex difference in the sensitivity of cardiac mitochondrial permeability transition pore to calcium load. Mol Cell Biochem 412:147–154CrossRefPubMedGoogle Scholar
  110. 110.
    Arieli Y, Gursahani H, Eaton MM, Hernandez LA, Schaefer S (2004) Gender modulation of Ca(2+) uptake in cardiac mitochondria. J Mol Cell Cardiol 37:507–513CrossRefPubMedGoogle Scholar
  111. 111.
    Yang SH, Liu R, Perez EJ, Wen Y, Stevens SM Jr, Valencia T, Brun-Zinkernagel AM, Prokai L, Will Y, Dykens J, Koulen P, Simpkins JW (2004) Mitochondrial localization of estrogen receptor beta. Proc Natl Acad Sci USA 101:4130–4135CrossRefPubMedGoogle Scholar
  112. 112.
    Zheng J, Ramirez VD (1999) Purification and identification of an estrogen binding protein from rat brain: oligomycin sensitivity-conferring protein (OSCP), a subunit of mitochondrial F0F1-ATP synthase/ATPase. J Steroid Biochem Mol Biol 68:65–75CrossRefPubMedGoogle Scholar
  113. 113.
    Moreno AJ, Moreira PI, Custodio JB, Santos MS (2013) Mechanism of inhibition of mitochondrial ATP synthase by 17beta-estradiol. J Bioenerg Biomembr 45:261–270CrossRefPubMedGoogle Scholar
  114. 114.
    Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Warne J, Pryce G, Hill JM, Shi X, Lenneras F, Puentes F, Kip M, Hilditch L, Walker P, Simone MI, Chan AW, Towers GJ, Coker AR, Duchen MR, Szabadkai G, Baker D, Selwood DL (2016) Selective inhibition of the mitochondrial permeability transition pore protects against neurodegeneration in experimental multiple sclerosis. J Biol Chem 291:4356–4373CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Feil Family Brain and Mind Research Institute, Weill Cornell MedicineNew YorkUSA
  2. 2.Weill Cornell Graduate School of Medical Sciences, Weill Cornell MedicineNew YorkUSA

Personalised recommendations