Mitochondrial and bioenergetic dysfunction in trauma-induced painful peripheral neuropathy

Molecular Pain

Ji Zhang³  Jack P. Antel¹  Seunghwan Lee³  Malena B. Rone¹  Tony K. Y. Lim² 

[1] Neurology and Neurosurgery, McGill University, Montreal H3A 2B4, QC, Canada;Alan Edwards Centre for Research on Pain, McGill University, 740 Docteur Penfield Ave, Suite 3200, Montreal H3A 0G1, QC, Canada;Faculty of Dentistry, McGill University, Montreal H3A 0C7, QC, Canada

关键词: Neuropathic pain;    Nerve injury;    Mitochondria;    Bioenergetics;   

Others  :  1228793
DOI  :  10.1186/s12990-015-0057-7

 received in 2015-07-05, accepted in 2015-08-26,  发布年份 2015

【 摘 要 】

Background

Mitochondrial dysfunction is observed in various neuropathic pain phenotypes, such as chemotherapy induced neuropathy, diabetic neuropathy, HIV-associated neuropathy, and in Charcot-Marie-Tooth neuropathy. To investigate whether mitochondrial dysfunction is present in trauma-induced painful mononeuropathy, a time-course of mitochondrial function and bioenergetics was characterized in the mouse partial sciatic nerve ligation model.

Results

Traumatic nerve injury induces increased metabolic indices of the nerve, resulting in increased oxygen consumption and increased glycolysis. Increased metabolic needs of the nerve are concomitant with bioenergetic and mitochondrial dysfunction. Mitochondrial dysfunction is characterized by reduced ATP synthase activity, reduced electron transport chain activity, and increased futile proton cycling. Bioenergetic dysfunction is characterized by reduced glycolytic reserve, reduced glycolytic capacity, and increased non-glycolytic acidification.

Conclusion

Traumatic peripheral nerve injury induces persistent mitochondrial and bioenergetic dysfunction which implies that pharmacological agents which seek to normalize mitochondrial and bioenergetic dysfunction could be expected to be beneficial for pain treatment. Increases in both glycolytic acidification and non-glycolytic acidification suggest that pH sensitive drugs which preferentially act on acidic tissue will have the ability to preferential act on injured nerves without affecting healthy tissues.

【 授权许可】

   
2015 Lim et al.

【 图 表 】

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【 参考文献 】

• [1]Bennett GJ, Doyle T, Salvemini D: Mitotoxicity in distal symmetrical sensory peripheral neuropathies. Nat Rev Neurol 2014, 10(6):326-336.
• [2]Flatters SJ: The contribution of mitochondria to sensory processing and pain. Prog Mol Biol Transl Sci 2015, 131:119-146.
• [3]Flatters SJ, Bennett GJ: Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain 2006, 122(3):245-257.
• [4]Sivitz WI, Yorek MA: Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal 2010, 12(4):537-577.
• [5]Dalakas MC, Semino-Mora C, Leon-Monzon M: Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2′3′-dideoxycytidine (ddC). Lab Invest 2001, 81(11):1537-1544.
• [6]Carter GT, Jensen MP, Galer BS, Kraft GH, Crabtree LD, Beardsley RM, Abresch RT, Bird TD: Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil 1998, 79(12):1560-1564.
• [7]Erecinska M, Silver IA: Ions and energy in mammalian brain. Prog Neurobiol 1994, 43(1):37-71.
• [8]Lim TK, Shi XQ, Johnson JM, Rone MB, Antel JP, David S, Zhang J: Peripheral nerve injury induces persistent vascular dysfunction and endoneurial hypoxia, contributing to the genesis of neuropathic pain. J Neurosci 2015, 35(8):3346-3359.
• [9]Murphy MP: How mitochondria produce reactive oxygen species. Biochem J 2009, 417(1):1-13.
• [10]Rizzuto R, De Stefani D, Raffaello A, Mammucari C: Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 2012, 13(9):566-578.
• [11]Kim HK, Park SK, Zhou JL, Taglialatela G, Chung K, Coggeshall RE, Chung JM: Reactive oxygen species (ROS) play an important role in a rat model of neuropathic pain. Pain 2004, 111(1–2):116-124.
• [12]Siau C, Bennett GJ: Dysregulation of cellular calcium homeostasis in chemotherapy-evoked painful peripheral neuropathy. Anesth Analg 2006, 102(5):1485-1490.
• [13]Brand MD, Nicholls DG: Assessing mitochondrial dysfunction in cells. Biochem J 2011, 435(2):297-312.
• [14]Steen KH, Steen AE, Kreysel HW, Reeh PW: Inflammatory mediators potentiate pain induced by experimental tissue acidosis. Pain 1996, 66(2–3):163-170.
• [15]Lim TK, Shi XQ, Martin HC, Huang H, Luheshi G, Rivest S et al. Blood-nerve barrier dysfunction contributes to the generation of neuropathic pain and allows targeting of injured nerves for pain relief. Pain. 2014;155(5):954–67.
• [16]Kim CF, Moalem-Taylor G: Detailed characterization of neuro-immune responses following neuropathic injury in mice. Brain Res 2011, 1405:95-108.
• [17]Solaini G, Harris DA: Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion. Biochem J 2005, 390(Pt 2):377-394.
• [18]Hill BG, Higdon AN, Dranka BP, Darley-Usmar VM: Regulation of vascular smooth muscle cell bioenergetic function by protein glutathiolation. Biochim Biophys Acta 2010, 1797(2):285-295.
• [19]Nicholls DG: Oxidative stress and energy crises in neuronal dysfunction. Ann N Y Acad Sci 2008, 1147:53-60.
• [20]Yadava N, Nicholls DG: Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity after partial respiratory inhibition of mitochondrial complex I with rotenone. J Neurosci 2007, 27(27):7310-7317.
• [21]Kim JW, Tchernyshyov I, Semenza GL, Dang CV: HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006, 3(3):177-185.
• [22]Chandel N, Budinger GR, Kemp RA, Schumacker PT: Inhibition of cytochrome-c oxidase activity during prolonged hypoxia. Am J Physiol 1995, 268(6 Pt 1):L918-L925.
• [23]Chandel NS, Budinger GR, Schumacker PT: Molecular oxygen modulates cytochrome C oxidase function. J Biol Chem 1996, 271(31):18672-18677.
• [24]Rolfe DF, Brand MD: Contribution of mitochondrial proton leak to skeletal muscle respiration and to standard metabolic rate. Am J Physiol 1996, 271(4 Pt 1):C1380-C1389.
• [25]Brookes PS: Mitochondrial H(+) leak and ROS generation: an odd couple. Free Radic Biol Med 2005, 38(1):12-23.
• [26]Piantadosi CA, Zhang J: Mitochondrial generation of reactive oxygen species after brain ischemia in the rat. Stroke 1996, 27(2):327-332.
• [27]Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC: HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006, 3(3):187-197.
• [28]Srivastava A, Mannam P: Warburg revisited: lessons for innate immunity and sepsis. Front Physiol 2015, 6:70.
• [29]Lage R, Dieguez C, Vidal-Puig A, Lopez M: AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med 2008, 14(12):539-549.
• [30]Wheaton WW, Chandel NS: Hypoxia. 2. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol 2011, 300(3):C385-C393.
• [31]Bedard K, Krause KH: The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 2007, 87(1):245-313.
• [32]Ives A, Nomura J, Martinon F, Roger T, LeRoy D, Miner JN, Simon G, Busso N, So A: Xanthine oxidoreductase regulates macrophage IL1beta secretion upon NLRP3 inflammasome activation. Nat Commun 2015, 6:6555.
• [33]Hunt JF, Fang K, Malik R, Snyder A, Malhotra N, Platts-Mills TA, Gaston B: Endogenous airway acidification. Implications for asthma pathophysiology. Am J Respir Crit Care Med 2000, 161(3 Pt 1):694-699.
• [34]Farr M, Garvey K, Bold AM, Kendall MJ, Bacon PA: Significance of the hydrogen ion concentration in synovial fluid in rheumatoid arthritis. Clin Exp Rheumatol 1985, 3(2):99-104.
• [35]Naghavi M, John R, Naguib S, Siadaty MS, Grasu R, Kurian KC, van Winkle WB, Soller B, Litovsky S, Madjid M, Willerson JT, Casscells W: pH heterogeneity of human and rabbit atherosclerotic plaques; a new insight into detection of vulnerable plaque. Atherosclerosis 2002, 164(1):27-35.
• [36]Biggs JE, Yates JM, Loescher AR, Clayton NM, Boissonade FM, Robinson PP: Changes in vanilloid receptor 1 (TRPV1) expression following lingual nerve injury. Eur J Pain 2007, 11(2):192-201.
• [37]Kim HY, Park CK, Cho IH, Jung SJ, Kim JS, Oh SB: Differential Changes in TRPV1 expression after trigeminal sensory nerve injury. J Pain 2008, 9(3):280-288.
• [38]Olson TH, Riedl MS, Vulchanova L, Ortiz-Gonzalez XR, Elde R: An acid sensing ion channel (ASIC) localizes to small primary afferent neurons in rats. Neuroreport 1998, 9(6):1109-1113.
• [39]Poirot O, Berta T, Decosterd I, Kellenberger S: Distinct ASIC currents are expressed in rat putative nociceptors and are modulated by nerve injury. J Physiol 2006, 576(Pt 1):215-234.
• [40]Komori T, Morikawa Y, Inada T, Hisaoka T, Senba E: Site-specific subtypes of macrophages recruited after peripheral nerve injury. Neuroreport 2011, 22(17):911-917.
• [41]Brombacher F, Arendse B, Peterson R, Holscher A, Holscher C: Analyzing classical and alternative macrophage activation in macrophage/neutrophil-specific IL-4 receptor-alpha-deficient mice. Methods Mol Biol 2009, 531:225-252.
• [42]Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG: Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 2009, 29(43):13435-13444.
• [43]Galvan-Pena S, O’Neill LA: Metabolic reprograming in macrophage polarization. Front Immunol 2014, 5:420.
• [44]Tavakoli S, Zamora D, Ullevig S, Asmis R: Bioenergetic profiles diverge during macrophage polarization: implications for the interpretation of 18F-FDG PET imaging of atherosclerosis. J Nucl Med 2013, 54(9):1661-1667.
• [45]Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, Wagner RA, Greaves DR, Murray PJ, Chawla A: Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 2006, 4(1):13-24.
• [46]Mills CD: M1 and M2 Macrophages: oracles of health and disease. Crit Rev Immunol 2012, 32(6):463-488.
• [47]Chiechio S, Caricasole A, Barletta E, Storto M, Catania MV, Copani A, Vertechy M, Nicolai R, Calvani M, Melchiorri D, Nicoletti F: L-Acetylcarnitine induces analgesia by selectively up-regulating mGlu2 metabotropic glutamate receptors. Mol Pharmacol 2002, 61(5):989-996.
• [48]Barrett TD, MacLeod BA, Walker MJ: RSD1019 suppresses ischaemia-induced monophasic action potential shortening and arrhythmias in anaesthetized rabbits. Br J Pharmacol 2000, 131(3):405-414.
• [49]Seltzer Z, Dubner R, Shir Y: A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990, 43(2):205-218.
• [50]Malmberg AB, Basbaum AI: Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates. Pain 1998, 76(1–2):215-222.