Skip to main content
SpringerLink
Log in

Mitochondrial Dysfunction in Ischemic Stroke

  • Chapter
  • First Online:
Translational Research in Stroke

Part of the book series: Translational Medicine Research ((TRAMERE))

Abstract

Mitochondrion is the powerhouse of the cell, which is essential for cell survival after cerebral ischemia/reperfusion. Mitochondrion is a sensitive organelle susceptible to brain ischemia/reperfusion injury. Mitochondrial dysfunction is one of the foremost events involved in brain ischemia/reperfusion process and then induces further damage to brain cells. It influences not only the fate of neural cells but also blood-brain barrier permeability after ischemic stroke. The underlying mechanism of mitochondria dysfunction in determining cell survival and cell death involves in many cell signaling pathways including apoptosis, autophagy, and mitochondrial biogenesis. Mitochondria apoptosis pathway was extensively explored in the past. Many apoptosis-related regulator families were involved in mitochondria apoptosis pathway, like Bcl-2 family, caspase family, p53 gene family, and so on. On the other hand, ROS injury, Ca2+ overload, and mPTP opening are also detrimental to mitochondrial function after cerebral ischemia/reperfusion. Recent interests were focused on the important role of mitophagy and mitochondrial biogenesis on cell survival after cerebral ischemia/reperfusion, which are thought to be endogenous protective mechanisms of mitochondrial dysfunction. Therefore, under ischemia/reperfusion conditions, promoting endogenous protective mechanisms and inhibiting exogenous damage mechanisms are both important therapeutic strategies. In summary, mitochondrial dysfunction is not simply the result of ischemia/reperfusion injury but also the cause of cascading damage. So, protecting dysfunctional mitochondria is pivotal to cell survival after ischemic stroke.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

AD:

Alzheimer’s disease

AIF:

Apoptosis-inducing factor

ALS:

Amyotrophic lateral sclerosis

Apaf-1:

Apoptotic protease-activating factor-1

ATP:

Adenosine triphosphate

BBB:

Blood-brain barrier

BER:

Base excision repair

BH:

Bcl-2 homology

CoA:

Coenzyme A

CsA:

Cyclosporine A

DETC-MeSO:

S-Methyl-N, N-diethyldithiocarbamate sulfoxide

ER:

Endoplasmic reticulum

ETC:

Electron transport chain

ETF:

Electron transfer flavoprotein

GPxs:

Glutathione peroxidases

H2O2 :

Hydrogen peroxide

IAP:

Inhibitor of apoptosis protein

IMM:

Inner mitochondrial membrane

IR:

Ischemia/reperfusion

IRI:

Ischemia/reperfusion injury

MA:

Malibatol A

MB:

Methylene blue

mCa2+ :

Mitochondrial Ca2+

MCAO:

Middle cerebral artery occlusion

MOMP:

Mitochondrial outer membrane permeabilization

mPTP:

Mitochondrial permeability transition pore

NO:

Nitric oxide

O2− :

Superoxide radical anions

OGD-R:

Oxygen-glucose deprivation and reoxygenation

OH-:

Hydroxyl radical

OMM:

Outer mitochondrial membrane

ONOO− :

Peroxynitrite species

OS:

Oxidative stress

OXPHOS:

Oxidative phosphorylation

PARP-1:

Poly(ADP-ribose) polymerase-1

PBR:

Peripheral benzodiazepine receptor

PD:

Parkinson’s disease

PhSe:

Diphenyl diselenide

PPAR:

Peroxisome proliferator-activated receptor

Prxs:

Peroxiredoxins

ROS:

Reactive oxygen species

Smac:

Second mitochondrial-derived activator of caspases

SOD:

Superoxide dismutases

THC:

Tetrahydrocannabinol

TNF:

Tumor necrosis factor

References

  1. Margulis L. Symbiotic theory of the origin of eukaryotic organelles; criteria for proof. Symp Soc Exp Biol. 1975;29:21–38.

    Google Scholar 

  2. Piper HM, Meuter K, Schafer C. Cellular mechanisms of ischemia-reperfusion injury. Ann Thorac Surg. 2003;75(2):S644–8.

    Article  PubMed  Google Scholar 

  3. Sims NR, Anderson MF. Mitochondrial contributions to tissue damage in stroke. Neurochem Int. 2002;40(6):511–26.

    Article  CAS  PubMed  Google Scholar 

  4. Kuroda S, Katsura KI, Tsuchidate R, Siesjo BK. Secondary bioenergetic failure after transient focal ischaemia is due to mitochondrial injury. Acta Physiol Scand. 1996;156(2):149–50.

    Article  CAS  PubMed  Google Scholar 

  5. Nakai A, Kuroda S, Kristian T, Siesjo BK. The immunosuppressant drug FK506 ameliorates secondary mitochondrial dysfunction following transient focal cerebral ischemia in the rat. Neurobiol Dis. 1997;4(3–4):288–300.

    Article  CAS  PubMed  Google Scholar 

  6. Anderson MF, Sims NR. Mitochondrial respiratory function and cell death in focal cerebral ischemia. J Neurochem. 1999;73(3):1189–99.

    Article  CAS  PubMed  Google Scholar 

  7. Polster BM, Fiskum G. Mitochondrial mechanisms of neural cell apoptosis. J Neurochem. 2004;90(6):1281–9.

    Article  CAS  PubMed  Google Scholar 

  8. Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005;39:359–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Camara AK, Lesnefsky EJ, Stowe DF. Potential therapeutic benefits of strategies directed to mitochondria. Antioxid Redox Signal. 2010;13(3):279–347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Antico Arciuch VG, Elguero ME, Poderoso JJ, Carreras MC. Mitochondrial regulation of cell cycle and proliferation. Antioxid Redox Signal. 2012;16(10):1150–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Marchenko ND, Moll UM. Mitochondrial death functions of p53. Mol Cell Oncol. 2014;1(2):e955995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science. 1998;281(5381):1305–8.

    Article  CAS  PubMed  Google Scholar 

  13. Jickling GC, Liu D, Stamova B, Ander BP, Zhan X, Lu A, et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab. 2014;34(2):185–99.

    Article  CAS  PubMed  Google Scholar 

  14. Cheranov SY, Jaggar JH. Mitochondrial modulation of Ca2+ sparks and transient KCa currents in smooth muscle cells of rat cerebral arteries. J Physiol. 2004;556(Pt 3):755–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003;4(5):399–415.

    Article  CAS  PubMed  Google Scholar 

  16. Jian Liu K, Rosenberg GA. Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med. 2005;39(1):71–80.

    Article  CAS  PubMed  Google Scholar 

  17. Narasimhan P, Liu J, Song YS, Massengale JL, Chan PH. VEGF stimulates the ERK 1/2 signaling pathway and apoptosis in cerebral endothelial cells after ischemic conditions. Stroke. 2009;40(4):1467–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Maier CM, Hsieh L, Crandall T, Narasimhan P, Chan PH. Evaluating therapeutic targets for reperfusion-related brain hemorrhage. Ann Neurol. 2006;59(6):929–38.

    Article  CAS  PubMed  Google Scholar 

  19. Maier CM, Hsieh L, Yu F, Bracci P, Chan PH. Matrix metalloproteinase-9 and myeloperoxidase expression: quantitative analysis by antigen immunohistochemistry in a model of transient focal cerebral ischemia. Stroke. 2004;35(5):1169–74.

    Article  CAS  PubMed  Google Scholar 

  20. Richter C, Kass GE. Oxidative stress in mitochondria: its relationship to cellular Ca2+ homeostasis, cell death, proliferation, and differentiation. Chem Biol Interact. 1991;77(1):1–23.

    Article  CAS  PubMed  Google Scholar 

  21. Halliwell B. Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging. 2001;18(9):685–716.

    Article  CAS  PubMed  Google Scholar 

  22. Olsen RK, Cornelius N, Gregersen N. Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism. J Inherit Metab Dis. 2015;38(4):703–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Drose S, Brandt U. Molecular mechanisms of superoxide production by the mitochondrial respiratory chain. Adv Exp Med Biol. 2012;748:145–69.

    Article  PubMed  CAS  Google Scholar 

  24. Goncalves RL, Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Brand MD. Sites of superoxide and hydrogen peroxide production by muscle mitochondria assessed ex vivo under conditions mimicking rest and exercise. J Biol Chem. 2015;290(1):209–27.

    Article  CAS  PubMed  Google Scholar 

  25. Bolisetty S, Jaimes EA. Mitochondria and reactive oxygen species: physiology and pathophysiology. Int J Mol Sci. 2013;14(3):6306–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hall CJ, Sanderson LE, Crosier KE, Crosier PS. Mitochondrial metabolism, reactive oxygen species, and macrophage function-fishing for insights. J Mol Med (Berl). 2014;92(11):1119–28.

    Article  CAS  Google Scholar 

  27. Ischiropoulos H. Oxidative modifications of alpha-synuclein. Ann N Y Acad Sci. 2003;991:93–100.

    Article  CAS  PubMed  Google Scholar 

  28. Factor VM, Kiss A, Woitach JT, Wirth PJ, Thorgeirsson SS. Disruption of redox homeostasis in the transforming growth factor-alpha/c-myc transgenic mouse model of accelerated hepatocarcinogenesis. J Biol Chem. 1998;273(25):15846–53.

    Article  CAS  PubMed  Google Scholar 

  29. Adams JM, Cory S. Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol. 2007;19(5):488–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9(1):47–59.

    Article  CAS  PubMed  Google Scholar 

  31. Merry DE, Korsmeyer SJ. Bcl-2 gene family in the nervous system. Annu Rev Neurosci. 1997;20:245–67.

    Article  CAS  PubMed  Google Scholar 

  32. Martin LJ. Biology of mitochondria in neurodegenerative diseases. Prog Mol Biol Transl Sci. 2012;107:355–415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479–89.

    Article  CAS  PubMed  Google Scholar 

  34. Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86(1):147–57.

    Article  CAS  PubMed  Google Scholar 

  35. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999;397(6718):441–6.

    Article  CAS  PubMed  Google Scholar 

  36. Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, et al. The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature. 2002;419(6905):367–74.

    Article  CAS  PubMed  Google Scholar 

  37. Janssens S, Tinel A. The PIDDosome, DNA-damage-induced apoptosis and beyond. Cell Death Differ. 2012;19(1):13–20.

    Article  CAS  PubMed  Google Scholar 

  38. Mate MJ, Ortiz-Lombardia M, Boitel B, Haouz A, Tello D, Susin SA, et al. The crystal structure of the mouse apoptosis-inducing factor AIF. Nat Struct Biol. 2002;9(6):442–6.

    Article  CAS  PubMed  Google Scholar 

  39. Wolff S, Erster S, Palacios G, Moll UM. p53’s mitochondrial translocation and MOMP action is independent of Puma and Bax and severely disrupts mitochondrial membrane integrity. Cell Res. 2008;18(7):733–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang S, Konorev EA, Kotamraju S, Joseph J, Kalivendi S, Kalyanaraman B. Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms. Intermediacy of H(2)O(2)- and p53-dependent pathways. J Biol Chem. 2004;279(24):25535–43.

    Article  CAS  PubMed  Google Scholar 

  41. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94(4):491–501.

    Article  CAS  PubMed  Google Scholar 

  42. Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR. The BCL-2 family reunion. Mol Cell. 2010;37(3):299–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schuler M, Green DR. Mechanisms of p53-dependent apoptosis. Biochem Soc Trans. 2001;29(Pt 6):684–8.

    Article  CAS  PubMed  Google Scholar 

  44. Vousden KH, Lu X. Live or let die: the cell’s response to p53. Nat Rev Cancer. 2002;2(8):594–604.

    Article  CAS  PubMed  Google Scholar 

  45. Liu X, Zou H, Slaughter C, Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997;89(2):175–84.

    Article  CAS  PubMed  Google Scholar 

  46. Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol. 1995;27(7):647–53.

    Article  CAS  PubMed  Google Scholar 

  47. Chan PH. Role of oxidants in ischemic brain damage. Stroke. 1996;27(6):1124–9.

    Article  CAS  PubMed  Google Scholar 

  48. Floyd RA, Carney JM. Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress. Ann Neurol. 1992;32(Suppl):S22–7.

    Article  CAS  PubMed  Google Scholar 

  49. Murakami K, Kondo T, Kawase M, Li Y, Sato S, Chen SF, et al. Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci. 1998;18(1):205–13.

    CAS  PubMed  Google Scholar 

  50. Liu PK, Grossman RG, Hsu CY, Robertson CS. Ischemic injury and faulty gene transcripts in the brain. Trends Neurosci. 2001;24(10):581–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen H, Hu CJ, He YY, Yang DI, Xu J, Hsu CY. Reduction and restoration of mitochondrial DNA content after focal cerebral ischemia/reperfusion. Stroke. 2001;32(10):2382–7.

    Article  CAS  PubMed  Google Scholar 

  52. Englander EW, Hu Z, Sharma A, Lee HM, Wu ZH, Greeley GH. Rat MYH, a glycosylase for repair of oxidatively damaged DNA, has brain-specific isoforms that localize to neuronal mitochondria. J Neurochem. 2002;83(6):1471–80.

    Article  CAS  PubMed  Google Scholar 

  53. Chen D, Minami M, Henshall DC, Meller R, Kisby G, Simon RP. Upregulation of mitochondrial base-excision repair capability within rat brain after brief ischemia. J Cereb Blood Flow Metab. 2003;23(1):88–98.

    Article  CAS  PubMed  Google Scholar 

  54. Li W, Luo Y, Zhang F, Signore AP, Gobbel GT, Simon RP, et al. Ischemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway. J Cereb Blood Flow Metab. 2006;26(2):181–98.

    Article  PubMed  CAS  Google Scholar 

  55. Li Q, Zhang T, Wang J, Zhang Z, Zhai Y, Yang GY, et al. Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke. Biochem Biophys Res Commun. 2014;444(2):182–8.

    Article  CAS  PubMed  Google Scholar 

  56. Zhang X, Yan H, Yuan Y, Gao J, Shen Z, Cheng Y, et al. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy. 2013;9(9):1321–33.

    Article  CAS  PubMed  Google Scholar 

  57. Li J, Ma X, Yu W, Lou Z, Mu D, Wang Y, et al. Reperfusion promotes mitochondrial dysfunction following focal cerebral ischemia in rats. PLoS One. 2012;7(9):e46498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Shi RY, Zhu SH, Li V, Gibson SB, Xu XS, Kong JM. BNIP3 interacting with LC3 triggers excessive mitophagy in delayed neuronal death in stroke. CNS Neurosci Ther. 2014;20(12):1045–55.

    Article  CAS  PubMed  Google Scholar 

  59. Zuo W, Zhang S, Xia CY, Guo XF, He WB, Chen NH. Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: the role of inhibition of Drp1 in ischemic brain damage. Neuropharmacology. 2014;86:103–15.

    Article  CAS  PubMed  Google Scholar 

  60. Zhang X, Yuan Y, Jiang L, Zhang J, Gao J, Shen Z, et al. Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: involvement of PARK2-dependent mitophagy. Autophagy. 2014;10(10):1801–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Anne Stetler R, Leak RK, Gao Y, Chen J. The dynamics of the mitochondrial organelle as a potential therapeutic target. J Cereb Blood Flow Metab. 2013;33(1):22–32.

    Article  CAS  PubMed  Google Scholar 

  62. Hock MB, Kralli A. Transcriptional control of mitochondrial biogenesis and function. Annu Rev Physiol. 2009;71:177–203.

    Article  CAS  PubMed  Google Scholar 

  63. Yin W, Signore AP, Iwai M, Cao G, Gao Y, Chen J. Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke. 2008;39(11):3057–63.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Chen SD, Lin TK, Lin JW, Yang DI, Lee SY, Shaw FZ, et al. Activation of calcium/calmodulin-dependent protein kinase IV and peroxisome proliferator-activated receptor gamma coactivator-1alpha signaling pathway protects against neuronal injury and promotes mitochondrial biogenesis in the hippocampal CA1 subfield after transient global ischemia. J Neurosci Res. 2010;88(14):3144–54.

    Article  CAS  PubMed  Google Scholar 

  65. Ekstrand MI, Falkenberg M, Rantanen A, Park CB, Gaspari M, Hultenby K, et al. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet. 2004;13(9):935–44.

    Article  CAS  PubMed  Google Scholar 

  66. Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev. 2008;88(2):611–38.

    Article  CAS  PubMed  Google Scholar 

  67. Song Z, Ghochani M, McCaffery JM, Frey TG, Chan DC. Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol Biol Cell. 2009;20(15):3525–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Vosler PS, Graham SH, Wechsler LR, Chen J. Mitochondrial targets for stroke: focusing basic science research toward development of clinically translatable therapeutics. Stroke. 2009;40(9):3149–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Desagher S, Glowinski J, Premont J. Pyruvate protects neurons against hydrogen peroxide-induced toxicity. J Neurosci. 1997;17(23):9060–7.

    CAS  PubMed  Google Scholar 

  70. Lee JY, Kim YH, Koh JY. Protection by pyruvate against transient forebrain ischemia in rats. J Neurosci. 2001;21(20):RC171.

    CAS  PubMed  Google Scholar 

  71. Christophe M, Nicolas S. Mitochondria: a target for neuroprotective interventions in cerebral ischemia-reperfusion. Curr Pharm Des. 2006;12(6):739–57.

    Article  CAS  PubMed  Google Scholar 

  72. Schwarzkopf TM, Koch K, Klein J. Reduced severity of ischemic stroke and improvement of mitochondrial function after dietary treatment with the anaplerotic substance triheptanoin. Neuroscience. 2015;300:201–9.

    Article  CAS  PubMed  Google Scholar 

  73. Liu RR, Murphy TH. Reversible cyclosporin A-sensitive mitochondrial depolarization occurs within minutes of stroke onset in mouse somatosensory cortex in vivo: a two-photon imaging study. J Biol Chem. 2009;284(52):36109–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Matsumoto S, Friberg H, Ferrand-Drake M, Wieloch T. Blockade of the mitochondrial permeability transition pore diminishes infarct size in the rat after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab. 1999;19(7):736–41.

    Article  CAS  PubMed  Google Scholar 

  75. Friberg H, Wieloch T. Mitochondrial permeability transition in acute neurodegeneration. Biochimie. 2002;84(2–3):241–50.

    Article  CAS  PubMed  Google Scholar 

  76. Rao VK, Carlson EA, Yan SS. Mitochondrial permeability transition pore is a potential drug target for neurodegeneration. Biochim Biophys Acta. 2014;1842(8):1267–72.

    Article  CAS  PubMed  Google Scholar 

  77. Waldmeier PC, Zimmermann K, Qian T, Tintelnot-Blomley M, Lemasters JJ. Cyclophilin D as a drug target. Curr Med Chem. 2003;10(16):1485–506.

    Article  CAS  PubMed  Google Scholar 

  78. Prentice H, Modi JP, Wu JY. Mechanisms of neuronal protection against excitotoxicity, endoplasmic reticulum stress, and mitochondrial dysfunction in stroke and neurodegenerative diseases. Oxidative Med Cell Longev. 2015;2015:964518.

    Article  Google Scholar 

  79. Zhang WH, Wang H, Wang X, Narayanan MV, Stavrovskaya IG, Kristal BS, et al. Nortriptyline protects mitochondria and reduces cerebral ischemia/hypoxia injury. Stroke. 2008;39(2):455–62.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Itzhak Y, Baker L, Norenberg MD. Characterization of the peripheral-type benzodiazepine receptors in cultured astrocytes: evidence for multiplicity. Glia. 1993;9(3):211–8.

    Article  CAS  PubMed  Google Scholar 

  81. Park CH, Carboni E, Wood PL, Gee KW. Characterization of peripheral benzodiazepine type sites in a cultured murine BV-2 microglial cell line. Glia. 1996;16(1):65–70.

    Article  CAS  PubMed  Google Scholar 

  82. Jayakumar AR, Panickar KS, Norenberg MD. Effects on free radical generation by ligands of the peripheral benzodiazepine receptor in cultured neural cells. J Neurochem. 2002;83(5):1226–34.

    Article  CAS  PubMed  Google Scholar 

  83. Perez Velazquez JL, Kokarovtseva L, Weisspapir M, Frantseva MV. Anti-porin antibodies prevent excitotoxic and ischemic damage to brain tissue. J Neurotrauma. 2003;20(7):633–47.

    Article  PubMed  Google Scholar 

  84. Villalobos MA, De La Cruz JP, Carrasco T, Smith-Agreda JM, de la Sanchez Cuesta F. Effects of alpha-tocopherol on lipid peroxidation and mitochondrial reduction of tetraphenyl tetrazolium in the rat brain. Brain Res Bull. 1994;33(3):313–8.

    Article  CAS  PubMed  Google Scholar 

  85. Mishima K, Tanaka T, Pu F, Egashira N, Iwasaki K, Hidaka R, et al. Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral infarction in mice. Neurosci Lett. 2003;337(1):56–60.

    Article  CAS  PubMed  Google Scholar 

  86. Banaclocha MM. Therapeutic potential of N-acetylcysteine in age-related mitochondrial neurodegenerative diseases. Med Hypotheses. 2001;56(4):472–7.

    Article  CAS  PubMed  Google Scholar 

  87. Sciamanna MA, Lee CP. Ischemia/reperfusion-induced injury of forebrain mitochondria and protection by ascorbate. Arch Biochem Biophys. 1993;305(2):215–24.

    Article  CAS  PubMed  Google Scholar 

  88. Reiter RJ, Guerrero JM, Garcia JJ, Acuna-Castroviejo D. Reactive oxygen intermediates, molecular damage, and aging. Relation to melatonin. Ann N Y Acad Sci. 1998;854:410–24.

    Article  CAS  PubMed  Google Scholar 

  89. Zini R, Morin C, Bertelli A, Bertelli AA, Tillement JP. Effects of resveratrol on the rat brain respiratory chain. Drugs Exp Clin Res. 1999;25(2–3):87–97.

    CAS  PubMed  Google Scholar 

  90. Morin C, Zini R, Albengres E, Bertelli AA, Bertelli A, Tillement JP. Evidence for resveratrol-induced preservation of brain mitochondria functions after hypoxia-reoxygenation. Drugs Exp Clin Res. 2003;29(5–6):227–33.

    CAS  PubMed  Google Scholar 

  91. Yang W, Chen X, Pan J, Ge H, Yin K, Wu Z, et al. Malibatol A protects against brain injury through reversing mitochondrial dysfunction in experimental stroke. Neurochem Int. 2015;80:33–40.

    Article  CAS  PubMed  Google Scholar 

  92. Wolff V, Schlagowski AI, Rouyer O, Charles AL, Singh F, Auger C, et al. Tetrahydrocannabinol induces brain mitochondrial respiratory chain dysfunction and increases oxidative stress: a potential mechanism involved in cannabis-related stroke. Biomed Res Int. 2015;2015:323706.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Li S, Wu C, Zhu L, Gao J, Fang J, Li D, et al. By improving regional cortical blood flow, attenuating mitochondrial dysfunction and sequential apoptosis galangin acts as a potential neuroprotective agent after acute ischemic stroke. Molecules. 2012;17(11):13403–23.

    Article  CAS  PubMed  Google Scholar 

  94. Weissig V. Mitochondrial-targeted drug and DNA delivery. Crit Rev Ther Drug Carrier Syst. 2003;20(1):1–62.

    Article  CAS  PubMed  Google Scholar 

  95. Dobrachinski F, da Silva MH, Tassi CL, de Carvalho NR, Dias GR, Golombieski RM, et al. Neuroprotective effect of diphenyl diselenide in a experimental stroke model: maintenance of redox system in mitochondria of brain regions. Neurotox Res. 2014;26(4):317–30.

    Article  CAS  PubMed  Google Scholar 

  96. Yang Y, Jiang S, Dong Y, Fan C, Zhao L, Yang X, et al. Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice. J Pineal Res. 2015;58(1):61–70.

    Article  CAS  PubMed  Google Scholar 

  97. Polster BM, Basanez G, Young M, Suzuki M, Fiskum G. Inhibition of Bax-induced cytochrome c release from neural cell and brain mitochondria by dibucaine and propranolol. J Neurosci. 2003;23(7):2735–43.

    CAS  PubMed  Google Scholar 

  98. Polster BM, Kinnally KW, Fiskum G. BH3 death domain peptide induces cell type-selective mitochondrial outer membrane permeability. J Biol Chem. 2001;276(41):37887–94.

    CAS  PubMed  Google Scholar 

  99. Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA. Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J Neurosci. 2010;30(3):1166–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shen Q, Du F, Huang S, Rodriguez P, Watts LT, Duong TQ. Neuroprotective efficacy of methylene blue in ischemic stroke: an MRI study. PLoS One. 2013;8(11):e79833.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Miclescu A, Sharma HS, Martijn C, Wiklund L. Methylene blue protects the cortical blood-brain barrier against ischemia/reperfusion-induced disruptions. Crit Care Med. 2010;38(11):2199–206.

    Article  CAS  PubMed  Google Scholar 

  102. Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan LJ, et al. Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem. 2011;286(18):16504–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Di Y, He YL, Zhao T, Huang X, Wu KW, Liu SH, et al. Methylene blue reduces acute cerebral ischemic injury via the induction of mitophagy. Mol Med. 2015;21:420–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China

    Qiang Li

  2. East Hospital, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200120, China

    Shane Gao

Authors
  1. Qiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shane Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qiang Li .

Editor information

Editors and Affiliations

  1. Department of Neurology & Neurosurgery, Cedars-Sinai Medical Center, Advanced Health Sciences Pavilion, Los Angeles, California, USA

    Paul A. Lapchak

  2. Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Guo-Yuan Yang

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.and Shanghai Jiao Tong University Press

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Li, Q., Gao, S. (2017). Mitochondrial Dysfunction in Ischemic Stroke. In: Lapchak, P., Yang, GY. (eds) Translational Research in Stroke. Translational Medicine Research. Springer, Singapore. https://doi.org/10.1007/978-981-10-5804-2_10

Download citation

Publish with us

Policies and ethics

Search

Navigation