Mitochondrial fission augments capsaicin-induced axonal degeneration

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• 作者：Hao Chiang (1) (2)
  Nobuhiko Ohno (2) (4)
  Yu-Lin Hsieh (1) (5)
  Don J. Mahad (2) (6)
  Shin Kikuchi (2) (7)
  Hitoshi Komuro (2)
  Sung-Tsang Hsieh (1) (3)
  Bruce D. Trapp (2)
  
  1. Department of Anatomy and Cell Biology ; National Taiwan University College of Medicine ; Taipei ; 10051 ; Taiwan
  2. Department of Neurosciences ; Lerner Research Institute ; Cleveland Clinic ; Cleveland ; OH ; 44195 ; USA
  4. Department of Anatomy and Molecular Histology ; University of Yamanashi ; Chuo ; Yamanashi ; 409-3898 ; Japan
  5. Department of Anatomy ; School of Medicine ; College of Medicine ; Kaohsiung Medical University ; Kaohsiung ; 80708 ; Taiwan
  6. Centre for Neuroregeneration ; University of Edinburgh ; Chancellor鈥檚 Building ; Edinburgh ; 49 Little France Crescent ; Edinburgh ; EH16 4SB ; UK
  7. Department of Anatomy 1 ; Sapporo Medical University School of Medicine ; West 17 ; South 1 ; Chuo-ku ; Sapporo ; 060-8556 ; Japan
  3. Department of Neurology ; National Taiwan University Hospital ; Taipei ; 10002 ; Taiwan
  
• 关键词：Mitochondria ; Axonal swellings ; Capsaicin ; Miro ; Drp1
• 刊名：Acta Neuropathologica
• 出版年：2015
• 出版时间：January 2015
• 年：2015
• 卷：129
• 期：1
• 页码：81-96
• 全文大小：8,499 KB
• 参考文献：1. Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS, Wissinger B (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26(2):211鈥?15. doi:10.1038/79944 CrossRef
  2. Amiri M, Hollenbeck PJ (2008) Mitochondrial biogenesis in the axons of vertebrate peripheral neurons. Dev Neurobiol 68(11):1348鈥?361. doi:10.1002/dneu.20668 CrossRef
  3. Anand P, Bley K (2011) Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8聽% patch. Br J Anaesth 107(4):490鈥?02. doi:10.1093/bja/aer260 CrossRef
  4. Barsoum MJ, Yuan H, Gerencser AA, Liot G, Kushnareva Y, Graber S, Kovacs I, Lee WD, Waggoner J, Cui J, White AD, Bossy B, Martinou JC, Youle RJ, Lipton SA, Ellisman MH, Perkins GA, Bossy-Wetzel E (2006) Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J 25(16):3900鈥?911. doi:10.1038/sj.emboj.7601253 CrossRef
  5. Beirowski B, Nogradi A, Babetto E, Garcia-Alias G, Coleman MP (2010) Mechanisms of axonal spheroid formation in central nervous system Wallerian degeneration. J Neuropathol Exp Neurol 69(5):455鈥?72. doi:10.1097/NEN.0b013e3181da84db CrossRef
  6. Blackstone C (2012) Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci 35:25鈥?7. doi:10.1146/annurev-neuro-062111-150400 CrossRef
  7. Bril V, England J, Franklin GM, Backonja M, Cohen J, Del TD, Feldman E, Iverson DJ, Perkins B, Russell JW, Zochodne D (2011) Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 76(20):1758鈥?765. doi:10.1212/WNL.0b013e3182166ebe CrossRef
  8. Bunker CB, Cerio R, Bull HA, Evans J, Dowd PM, Foreman JC (1991) The effect of capsaicin application on mast cells in normal human skin. Agents Actions 33(1鈥?):195鈥?96 CrossRef
  9. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389(6653):816鈥?24. doi:10.1038/39807 CrossRef
  10. Cereghetti GM, Stangherlin A, de Martins BO, Chang CR, Blackstone C, Bernardi P, Scorrano L (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci U S A 105(41):15803鈥?5808. doi:10.1073/pnas.0808249105 CrossRef
  11. Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125(7):1241鈥?252. doi:10.1016/j.cell.2006.06.010 CrossRef
  12. Chang CR, Blackstone C (2010) Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann N Y Acad Sci 1201:34鈥?9. doi:10.1111/j.1749-6632.2010.05629.x CrossRef
  13. Chen H, Chan DC (2009) Mitochondrial dynamics-fusion, fission, movement, and mitophagy鈥攊n neurodegenerative diseases. Hum Mol Genet 18(R2):R169鈥揜176. doi:10.1093/hmg/ddp326 CrossRef
  14. Cho B, Choi SY, Cho HM, Kim HJ, Sun W (2013) Physiological and pathological significance of dynamin-related protein 1 (drp1)-dependent mitochondrial fission in the nervous system. Exp Neurobiol 22(3):149鈥?57. doi:10.5607/en.2013.22.3.149 CrossRef
  15. Chowdhury SK, Smith DR, Fernyhough P (2013) The role of aberrant mitochondrial bioenergetics in diabetic neuropathy. Neurobiol Dis 51:56鈥?5. doi:10.1016/j.nbd.2012.03.016 CrossRef
  16. Davies JW, Hainsworth AH, Guerin CJ, Lambert DG (2010) Pharmacology of capsaicin-, anandamide-, and / N-arachidonoyl-dopamine-evoked cell death in a homogeneous transient receptor potential vanilloid subtype 1 receptor population. Br J Anaesth 104(5):596鈥?02. doi:10.1093/bja/aeq067 CrossRef
  17. Deluca GC, Ebers GC, Esiri MM (2004) The extent of axonal loss in the long tracts in hereditary spastic paraplegia. Neuropathol Appl Neurobiol 30(6):576鈥?84. doi:10.1111/j.1365-2990.2004.00587.x CrossRef
  18. Derry S, Sven-Rice A, Cole P, Tan T, Moore RA (2013) Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Datab Syst Rev 2:CD007393. doi:10.1002/14651858.CD007393.pub3
  19. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1(4):515鈥?25 (S1534-5807(01)00055-7 [pii]) CrossRef
  20. Fransson A, Ruusala A, Aspenstrom P (2003) Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J Biol Chem 278(8):6495鈥?502. doi:10.1074/jbc.M208609200 CrossRef
  21. Frezza C, Cipolat S, de Martins BO, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS, Danial NN, De SB, Scorrano L (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126(1):177鈥?89. doi:10.1016/j.cell.2006.06.025 CrossRef
  22. Germain M, Mathai JP, McBride HM, Shore GC (2005) Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis. EMBO J 24(8):1546鈥?556. doi:10.1038/sj.emboj.7600592 CrossRef
  23. Gibbons CH, Wang N, Freeman R (2010) Capsaicin induces degeneration of cutaneous autonomic nerve fibers. Ann Neurol 68(6):888鈥?98. doi:10.1002/ana.22126 CrossRef
  24. Gomes LC, Di BG, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13(5):589鈥?98. doi:10.1038/ncb2220 CrossRef
  25. Grohm J, Kim SW, Mamrak U, Tobaben S, Cassidy-Stone A, Nunnari J, Plesnila N, Culmsee C (2012) Inhibition of Drp1 provides neuroprotection in vitro and in vivo. Cell Death Differ 19(9):1446鈥?458. doi:10.1038/cdd.2012.18 CrossRef
  26. Han XJ, Lu YF, Li SA, Kaitsuka T, Sato Y, Tomizawa K, Nairn AC, Takei K, Matsui H, Matsushita M (2008) CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol 182(3):573鈥?85. doi:10.1083/jcb.200802164 CrossRef
  27. Harti G, Sharkey KA, Pierau FK (1989) Effects of capsaicin in rat and pigeon on peripheral nerves containing substance P and calcitonin gene-related peptide. Cell Tissue Res 256(3):465鈥?74 CrossRef
  28. Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, Ohnishi A, Hayasaka K, Onodera O, Baba M, Yasuda H, Saito T, Nakashima K, Kira J, Kaji R, Oka N, Sobue G (2003) Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain 126(Pt 1):134鈥?51 CrossRef
  29. Hoeijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG (2012) Small-fibre neuropathies鈥攁dvances in diagnosis, pathophysiology and management. Nat Rev Neurol 8(7):369鈥?79. doi:10.1038/nrneurol.2012.97 CrossRef
  30. Hoyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, Bianchi K, Fehrenbacher N, Elling F, Rizzuto R, Mathiasen IS, Jaattela M (2007) Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 25(2):193鈥?05. doi:10.1016/j.molcel.2006.12.009 CrossRef
  31. Hsieh ST, Chiang HY, Lin WM (2000) Pathology of nerve terminal degeneration in the skin. J Neuropathol Exp Neurol 59(4):297鈥?07
  32. Ikegami K, Koike T (2003) Non-apoptotic neurite degeneration in apoptotic neuronal death: pivotal role of mitochondrial function in neurites. Neuroscience 122(3):617鈥?26 CrossRef
  33. Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki SO, Masuda K, Otera H, Nakanishi Y, Nonaka I, Goto Y, Taguchi N, Morinaga H, Maeda M, Takayanagi R, Yokota S, Mihara K (2009) Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol 11(8):958鈥?66. doi:10.1038/ncb1907 CrossRef
  34. Jahani-Asl A, Pilon-Larose K, Xu W, MacLaurin JG, Park DS, McBride HM, Slack RS (2011) The mitochondrial inner membrane GTPase, optic atrophy 1 (Opa1), restores mitochondrial morphology and promotes neuronal survival following excitotoxicity. J Biol Chem 286(6):4772鈥?782. doi:10.1074/jbc.M110.167155 CrossRef
  35. Kennedy WR, Wendelschafer-Crabb G, Johnson T (1996) Quantitation of epidermal nerves in diabetic neuropathy. Neurology 47(4):1042鈥?048 CrossRef
  36. Kim SR, Lee DY, Chung ES, Oh UT, Kim SU, Jin BK (2005) Transient receptor potential vanilloid subtype 1 mediates cell death of mesencephalic dopaminergic neurons in vivo and in vitro. J Neurosci 25(3):662鈥?71. doi:10.1523/JNEUROSCI.4166-04.2005 CrossRef
  37. Kiryu-Seo S, Ohno N, Kidd GJ, Komuro H, Trapp BD (2010) Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. J Neurosci 30(19):6658鈥?666. doi:10.1523/JNEUROSCI.5265-09.2010 CrossRef
  38. Knott AB, Bossy-Wetzel E (2008) Impairing the mitochondrial fission and fusion balance: a new mechanism of neurodegeneration. Ann N Y Acad Sci 1147:283鈥?92. doi:10.1196/annals.1427.030 CrossRef
  39. Ko MH, Chen WP, Hsieh ST (2002) Neuropathology of skin denervation in acrylamide-induced neuropathy. Neurobiol Dis 11(1):155鈥?65 (S0969996102905371 [pii]) CrossRef
  40. Labrousse AM, Zappaterra MD, Rube DA, van der Bliek AM (1999) / C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol Cell 4(5):815鈥?26 (S1097-2765(00)80391-3 [pii]) CrossRef
  41. Lackner LL, Nunnari JM (2009) The molecular mechanism and cellular functions of mitochondrial division. Biochim Biophys Acta 1792(12):1138鈥?144. doi:10.1016/j.bbadis.2008.11.011 CrossRef
  42. Lauria G, Morbin M, Lombardi R, Borgna M, Mazzoleni G, Sghirlanzoni A, Pareyson D (2003) Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies. Neurology 61(5):631鈥?36 CrossRef
  43. Lauria G, Morbin M, Lombardi R, Capobianco R, Camozzi F, Pareyson D, Manconi M, Geppetti P (2006) Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and in painful neuropathies. J Peripher Nerv Syst 11(3):262鈥?71. doi:10.1111/j.1529-8027.2006.0097.x CrossRef
  44. Legros F, Lombes A, Frachon P, Rojo M (2002) Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol Biol Cell 13(12):4343鈥?354. doi:10.1091/mbc.E02-06-0330 CrossRef
  45. Lynn B (1990) Capsaicin: actions on nociceptive C-fibres and therapeutic potential. Pain 41(1):61鈥?9 (0304-3959(90)91110-5 [pii]) CrossRef
  46. Macaskill AF, Rinholm JE, Twelvetrees AE, Arancibia-Carcamo IL, Muir J, Fransson A, Aspenstrom P, Attwell D, Kittler JT (2009) Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron 61(4):541鈥?55. doi:10.1016/j.neuron.2009.01.030 CrossRef
  47. Marsh SJ, Stansfeld CE, Brown DA, Davey R, McCarthy D (1987) The mechanism of action of capsaicin on sensory C-type neurons and their axons in vitro. Neuroscience 23(1):275鈥?89 CrossRef
  48. Misko AL, Sasaki Y, Tuck E, Milbrandt J, Baloh RH (2012) Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration. J Neurosci 32(12):4145鈥?155. doi:10.1523/JNEUROSCI.6338-11.2012 CrossRef
  49. Nakai J, Ohkura M, Imoto K (2001) A high signal-to-noise Ca(2+) probe composed of a single green fluorescent protein. Nat Biotechnol 19(2):137鈥?41. doi:10.1038/84397 CrossRef
  50. Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM, Bruck W, Bishop D, Misgeld T, Kerschensteiner M (2011) A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 17(4):495鈥?99. doi:10.1038/nm.2324 CrossRef
  51. Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GM, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG (2014) Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343(6170):506鈥?11. doi:10.1126/science.1247363 CrossRef
  52. Ohno N, Kidd GJ, Mahad D, Kiryu-Seo S, Avishai A, Komuro H, Trapp BD (2011) Myelination and axonal electrical activity modulate the distribution and motility of mitochondria at CNS nodes of Ranvier. J Neurosci 31(20):7249鈥?258. doi:10.1523/JNEUROSCI.0095-11.2011 CrossRef
  53. Pareyson D (2004) Differential diagnosis of Charcot-Marie-Tooth disease and related neuropathies. Neurol Sci 25(2):72鈥?2. doi:10.1007/s10072-004-0233-4 CrossRef
  54. Perkins GA, Ellisman MH (2011) Mitochondrial configurations in peripheral nerve suggest differential ATP production. J Struct Biol 173(1):117鈥?27. doi:10.1016/j.jsb.2010.06.017 CrossRef
  55. Qi X, Disatnik MH, Shen N, Sobel RA, Mochly-Rosen D (2011) Aberrant mitochondrial fission in neurons induced by protein kinase C{delta} under oxidative stress conditions in vivo. Mol Biol Cell 22(2):256鈥?65. doi:10.1091/mbc.E10-06-0551 CrossRef
  56. Raff MC, Whitmore AV, Finn JT (2002) Axonal self-destruction and neurodegeneration. Science 296(5569):868鈥?71. doi:10.1126/science.1068613 CrossRef
  57. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J (2011) Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 108(25):10190鈥?0195. doi:10.1073/pnas.1107402108 CrossRef
  58. Richardson JD, Vasko MR (2002) Cellular mechanisms of neurogenic inflammation. J Pharmacol Exp Ther 302(3):839鈥?45. doi:10.1124/jpet.102.032797 CrossRef
  59. Rugarli EI, Langer T (2012) Mitochondrial quality control: a matter of life and death for neurons. EMBO J 31(6):1336鈥?349. doi:10.1038/emboj.2012.38 CrossRef
  60. Saotome M, Safiulina D, Szabadkai G, Das S, Fransson A, Aspenstrom P, Rizzuto R, Hajnoczky G (2008) Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci USA 105(52):20728鈥?0733. doi:10.1073/pnas.0808953105 CrossRef
  61. Saxton WM, Hollenbeck PJ (2012) The axonal transport of mitochondria. J Cell Sci 125(Pt 9):2095鈥?104. doi:10.1242/jcs.053850 CrossRef
  62. Schwarz TL (2013) Mitochondrial trafficking in neurons. Cold Spring Harb Perspect Biol 5 (6). doi:10.1101/cshperspect.a011304
  63. Sheng ZH, Cai Q (2012) Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci 13(2):77鈥?3. doi:10.1038/nrn3156 CrossRef
  64. Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR (1998) Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci 18(21):8947鈥?959
  65. Sivitz WI, Yorek MA (2010) Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal 12(4):537鈥?77. doi:10.1089/ars.2009.2531 CrossRef
  66. Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM (1998) A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol 143(2):351鈥?58 CrossRef
  67. Stys PK (2005) General mechanisms of axonal damage and its prevention. J Neurol Sci 233(1鈥?):3鈥?3. doi:10.1016/j.jns.2005.03.031 CrossRef
  68. Szabadkai G, Simoni AM, Chami M, Wieckowski MR, Youle RJ, Rizzuto R (2004) Drp-1-dependent division of the mitochondrial network blocks intraorganellar Ca2+ waves and protects against Ca2+-mediated apoptosis. Mol Cell 16(1):59鈥?8. doi:10.1016/j.molcel.2004.09.026 CrossRef
  69. Taylor AM, Blurton-Jones M, Rhee SW, Cribbs DH, Cotman CW, Jeon NL (2005) A microfluidic culture platform for CNS axonal injury, regeneration and transport. Nat Methods 2(8):599鈥?05. doi:10.1038/nmeth777 CrossRef
  70. Thompson RJ, Doran JF, Jackson P, Dhillon AP, Rode J (1983) PGP 9.5鈥攁 new marker for vertebrate neurons and neuroendocrine cells. Brain Res 278(1鈥?):224鈥?28 CrossRef
  71. Thresh JC (1876) Capsaicin, the active principle in Capsicum fruits. Pharm J Trans 3(315):21
  72. Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, Da CS, Clerc P, Raschke I, Merkwirth C, Ehses S, Krause F, Chan DC, Alexander C, Bauer C, Youle R, Langer T, Martinou JC (2009) SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 28(11):1589鈥?600. doi:10.1038/emboj.2009.89 CrossRef
  73. Trapp BD, Stys PK (2009) Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 8(3):280鈥?91. doi:10.1016/S1474-4422(09)70043-2 CrossRef
  74. van der Bliek AM, Redelmeier TE, Damke H, Tisdale EJ, Meyerowitz EM, Schmid SL (1993) Mutations in human dynamin block an intermediate stage in coated vesicle formation. J Cell Biol 122(3):553鈥?63 CrossRef
  75. Verburg J, Hollenbeck PJ (2008) Mitochondrial membrane potential in axons increases with local nerve growth factor or semaphorin signaling. J Neurosci 28(33):8306鈥?315. doi:10.1523/JNEUROSCI.2614-08.2008 CrossRef
  76. Wakabayashi J, Zhang Z, Wakabayashi N, Tamura Y, Fukaya M, Kensler TW, Iijima M, Sesaki H (2009) The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J Cell Biol 186(6):805鈥?16. doi:10.1083/jcb.200903065 CrossRef
  77. Wang JT, Medress ZA, Barres BA (2012) Axon degeneration: molecular mechanisms of a self-destruction pathway. J Cell Biol 196(1):7鈥?8. doi:10.1083/jcb.201108111 CrossRef
  78. Wang X, Schwarz TL (2009) The mechanism of Ca2+-dependent regulation of kinesin-mediated mitochondrial motility. Cell 136(1):163鈥?74. doi:10.1016/j.cell.2008.11.046 CrossRef
  79. Yang Y, Coleman M, Zhang L, Zheng X, Yue Z (2013) Autophagy in axonal and dendritic degeneration. Trends Neurosci 36(7):418鈥?28. doi:10.1016/j.tins.2013.04.001 CrossRef
  80. Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12(1):9鈥?4. doi:10.1038/nrm3028 CrossRef
  81. Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schroder JM, Vance JM (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36(5):449鈥?51. doi:10.1038/ng1341 CrossRef
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Pathology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0533

文摘

Capsaicin, an agonist of transient receptor potential vanilloid receptor 1, induces axonal degeneration of peripheral sensory nerves and is commonly used to treat painful sensory neuropathies. In this study, we investigated the role of mitochondrial dynamics in capsaicin-induced axonal degeneration. In capsaicin-treated rodent sensory axons, axonal swellings, decreased mitochondrial stationary site length and reduced mitochondrial transport preceded axonal degeneration. Increased axoplasmic Ca2+ mediated the alterations in mitochondrial length and transport. While sustaining mitochondrial transport did not reduce axonal swellings in capsaicin-treated axons, preventing mitochondrial fission by overexpression of mutant dynamin-related protein 1 increased mitochondrial length, retained mitochondrial membrane potentials and reduced axonal loss upon capsaicin treatment. These results establish that mitochondrial stationary site size significantly affects axonal integrity and suggest that inhibition of Ca2+-dependent mitochondrial fission facilitates mitochondrial function and axonal survival following activation of axonal cationic channels.