The disruption of mitochondrial axonal transport is an early event in neuroinflammation

Journal of Neuroinflammation

Pablo Villoslada³  Pablo M. Garcia-Roves¹  Alba Gonzalez-Franquesa⁴  Beatriz Moreno²  Oihana Errea² 

[1] Department of Physiological Sciences II, University of Barcelona, Barcelona, 08907, Spain;Center of Neuroimmunology, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Cellex Building, Laboratory 3A, Casanova 145, Barcelona, 08036, Spain;University of California, San Francisco, USA;Diabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, 08036, Spain

关键词: Multiple sclerosis;    Oxidative stress;    Inflammation;    Axonal damage;    Axonal transport;    Mitochondria;   

Others  :  1227075
DOI  :  10.1186/s12974-015-0375-8

 received in 2015-04-21, accepted in 2015-08-16,  发布年份 2015

【 摘 要 】

Background

In brain inflammatory diseases, axonal damage is one of the most critical steps in the cascade that leads to permanent disability. Thus, identifying the initial events triggered by inflammation or oxidative stress that provoke axonal damage is critical for the development of neuroprotective therapies. Energy depletion due to mitochondrial dysfunction has been postulated as an important step in the damage of axons. This prompted us to study the effects of acute inflammation and oxidative stress on the morphology, transport, and function of mitochondria in axons.

Methods

Mouse cerebellar slice cultures were challenged with either lipopolysaccharide (LPS) or hydrogen peroxide (H ₂ O ₂ ) ex vivo for 24 h. Axonal mitochondrial morphology was evaluated by transmission electron microscopy (TEM) and mitochondrial transportation by time-lapse imaging. In addition, mitochondrial function in the cerebellar slice cultures was analyzed through high-resolution respirometry assays and quantification of adenosine triphosphate (ATP) production.

Results

Both conditions promoted an increase in the size and complexity of axonal mitochondria evident in electron microscopy images, suggesting a compensatory response. Such compensation was reflected at the tissue level as increased respiratory activity of complexes I and IV and as a transient increase in ATP production in response to acute inflammation. Notably, time-lapse microscopy indicated that mitochondrial transport (mean velocity) was severely impaired in axons, increasing the proportion of stationary mitochondria in axons after LPS challenge. Indeed, the two challenges used produced different effects: inflammation mostly reducing retrograde transport and oxidative stress slightly enhancing retrograde transportation.

Conclusions

Neuroinflammation acutely impairs axonal mitochondrial transportation, which would promote an inappropriate delivery of energy throughout axons and, by this way, contribute to axonal damage. Thus, preserving axonal mitochondrial transport might represent a promising avenue to exploit as a therapeutic target for neuroprotection in brain inflammatory diseases like multiple sclerosis.

【 授权许可】

   
2015 Errea et al.

【 图 表 】

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【 参考文献 】

• [1]Ferguson B, Matyszak MK, Esiri MM, Perry VH: Axonal damage in acute multiple sclerosis lesions. Brain 1997, 120(Pt 3):393-9.
• [2]Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L: Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998, 338:278-85.
• [3]Filippi M, Bozzali M, Rovaris M, Gonen O, Kesavadas C, Ghezzi A, Martinelli V, Grossman RI, Scotti G, Comi G, Falini A: Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 2003, 126:433-7.
• [4]Trapp BD, Ransohoff R, Rudick R: Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 1999, 12:295-302.
• [5]Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H: Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 2000, 157:267-76.
• [6]Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W: Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002, 125:2202-12.
• [7]Liu JS, Zhao ML, Brosnan CF, Lee SC: Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am J Pathol 2001, 158:2057-66.
• [8]Smith KJ, Lassmann H: The role of nitric oxide in multiple sclerosis. Lancet Neurol 2002, 1:232-41.
• [9]Lassmann H: Multiple sclerosis: lessons from molecular neuropathology. Exp Neurol 2014, 262PA:2-7.
• [10]Waxman SG: Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci 2006, 7:932-41.
• [11]Nave K-AA, Trapp BD: Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci 2008, 31:535-61.
• [12]Simons M, Misgeld T, Kerschensteiner M: A unified cell biological perspective on axon-myelin injury. J Cell Biol 2014, 206:335-45.
• [13]Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM, Bruck W, Bishop D, Misgeld T, Kerschensteiner M: A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 2011, 17:495-9.
• [14]Ghafourifar P, Mousavizadeh K, Parihar MS, Nazarewicz RR, Parihar A, Zenebe WJ: Mitochondria in multiple sclerosis. Front Biosci 2008, 13:3116-26.
• [15]Campbell GR, Worrall JT, Mahad DJ: The central role of mitochondria in axonal degeneration in multiple sclerosis. Mult Scler 2014, 20:1806-13.
• [16]Witte ME, Mahad DJ, Lassmann H, van Horssen J: Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol Med 2014, 20:179-87.
• [17]Mahad DJ, Ziabreva I, Lassmann H, Turnbull D: Mitochondrial defects in acute multiple sclerosis lesions. Brain 2008, 131:1722-35.
• [18]Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD: Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 2006, 59:478-89.
• [19]Sorbara CD, Wagner NE, Ladwig A, Nikic I, Merkler D, Kleele T, Marinkovic P, Naumann R, Godinho L, Bareyre FM, Bishop D, Misgeld T, Kerschensteiner M: Pervasive axonal transport deficits in multiple sclerosis models. Neuron 2014, 84:1183-90.
• [20]Di Penta A, Moreno B, Reix S, Fernandez-Diez B, Villanueva M, Errea O, Escala N, Vandenbroeck K, Comella JX, Villoslada P: Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation. PloS ONE 2013, 8:e54722.
• [21]Dickey AS, Strack S: PKA/AKAP1 and PP2A/Bbeta2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics. J Neurosci 2011, 31:15716-26.
• [22]Picard M, White K, Turnbull DM: Mitochondrial morphology, topology, and membrane interactions in skeletal muscle: a quantitative three-dimensional electron microscopy study. J App Physiol 2013, 114:161-71.
• [23]Kiryu-Seo S, Ohno N, Kidd GJ, Komuro H, Trapp BD: Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. J Neurosci 2010, 30:6658-66.
• [24]Kasri NN, Govek EE, Van Aelst L: Characterization of oligophrenin-1, a RhoGAP lost in patients affected with mental retardation: lentiviral injection in organotypic brain slice cultures. Methods Enzymol 2008, 439:255-66.
• [25]Ohno N, Kidd GJ, Mahad D, Kiryu-Seo S, Avishai A, Komuro H, Trapp BD: Myelination and axonal electrical activity modulate the distribution and motility of mitochondria at CNS nodes of Ranvier. J Neurosci 2011, 31:7249-58.
• [26]Gnaiger E, Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Steurer W, Margreiter R, et al.: Mitochondria in the cold. In Life in the cold. Edited by Heldmaier G. Springer, Berlin Heidelberg; 2000:431-42.
• [27]Mannella CA: Structure and dynamics of the mitochondrial inner membrane cristae. Biochim Biophys Acta 2006, 1763:542-8.
• [28]Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Casarin A, Gomes LC, Perales-Clemente E, Salviati L, Fernandez-Silva P, Enriquez JA, Scorrano L: Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 2013, 155:160-71.
• [29]Zhang CL, Ho PL, Kintner DB, Sun D, Chiu SY: Activity-dependent regulation of mitochondrial motility by calcium and Na/K-ATPase at nodes of Ranvier of myelinated nerves. J Neurosci 2010, 30:3555-66.
• [30]Chiu SY: Matching mitochondria to metabolic needs at nodes of Ranvier. Neuroscientist 2011, 17:343-50.
• [31]Fischer F, Hamann A, Osiewacz HD: Mitochondrial quality control: an integrated network of pathways. Trends Biochem Sci 2012, 37:284-92.
• [32]Hollenbeck PJ, Saxton WM: The axonal transport of mitochondria. J Cell Sci 2005, 118:5411-9.
• [33]Sheng ZH, Cai Q: Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci 2012, 13:77-93.
• [34]Pathak D, Sepp KJ, Hollenbeck PJ: Evidence that myosin activity opposes microtubule-based axonal transport of mitochondria. J Neurosci 2010, 30:8984-92.
• [35]Lassmann H, van Horssen J: The molecular basis of neurodegeneration in multiple sclerosis. FEBS Lett 2011, 585:3715-23.
• [36]Davies AL, Desai RA, Bloomfield PS, McIntosh PR, Chapple KJ, Linington C, Fairless R, Diem R, Kasti M, Murphy MP, Smith KJ: Neurological deficits caused by tissue hypoxia in neuroinflammatory disease. Ann Neurol 2013, 74:815-25.
• [37]Lambert AJ, Brand MD: Reactive oxygen species production by mitochondria. Meth Mol Biol 2009, 554:165-81.
• [38]Turrens JF: Mitochondrial formation of reactive oxygen species. J Physiol 2003, 552:335-44.
• [39]Venditti P, Di Stefano L, Di Mateo S: Mitochondrial metabolism of reactive oxygen species. Mitochondrion 2013, 13:71-82.
• [40]Morris RL, Hollenbeck PJ: The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth. J Cell Sci 1993, 104(Pt 3):917-27.
• [41]Ruthel G, Hollenbeck PJ: Response of mitochondrial traffic to axon determination and differential branch growth. J Neurosci 2003, 23:8618-24.
• [42]Waxman SG: Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status. Nat Clin Pract Neurol 2008, 4:159-69.
• [43]Misgeld T, Kerschensteiner M, Bareyre FM, Burgess RW, Lichtman JW: Imaging axonal transport of mitochondria in vivo. Nat Methods 2007, 4:559-61.
• [44]Mahad DJ, Ziabreva I, Campbell G, Lax N, White K, Hanson PS, Lassmann H, Turnbull DM: Mitochondrial changes within axons in multiple sclerosis. Brain 2009, 132:1161-74.