Abstract
Formation of myelin sheaths by Schwann cells (SCs) enables rapid and efficient transmission of action potentials in peripheral axons, and disruption of myelination results in disorders that involve decreased sensory and motor functions. Given that construction of SC myelin requires high levels of lipid and protein synthesis, mitochondria, which are pivotal in cellular metabolism, may be potential regulators of the formation and maintenance of SC myelin. Supporting this notion, abnormal mitochondria are found in SCs of neuropathic peripheral nerves in both human patients and the relevant animal models. However, evidence for the importance of SC mitochondria in myelination has been limited, until recently. Several studies have recently used genetic approaches that allow SC-specific ablation of mitochondrial metabolic activity in living animals to show the critical roles of SC mitochondria in the development and maintenance of peripheral nerve axons. Here, we review current knowledge about the involvement of SC mitochondria in the formation and dysfunction of myelinated axons in the peripheral nervous system.
Similar content being viewed by others
References
Sherman DL, Brophy PJ (2005) Mechanisms of axon ensheathment and myelin growth. Nat Rev Neurosci 6(9):683–690. doi:10.1038/nrn1743
Jessen KR, Mirsky R (2008) Negative regulation of myelination: relevance for development, injury, and demyelinating disease. Glia 56(14):1552–1565. doi:10.1002/glia.20761
Decker L, Desmarquet-Trin-Dinh C, Taillebourg E, Ghislain J, Vallat JM, Charnay P (2006) Peripheral myelin maintenance is a dynamic process requiring constant Krox20 expression. J Neurosci 26(38):9771–9779. doi:10.1523/JNEUROSCI.0716-06.2006
Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283(5407):1482–1488
Schapira AH (2006) Mitochondrial disease. Lancet 368(9529):70–82. doi:10.1016/S0140-6736(06)68970-8
Schapira AH (2012) Mitochondrial diseases. Lancet 379(9828):1825–1834. doi:10.1016/S0140-6736(11)61305-6
Schroder JM, Sommer C (1991) Mitochondrial abnormalities in human sural nerves: fine structural evaluation of cases with mitochondrial myopathy, hereditary and non-hereditary neuropathies, and review of the literature. Acta Neuropathol 82(6):471–482
Schroder JM (1993) Neuropathy associated with mitochondrial disorders. Brain Pathol 3(2):177–190
Pareyson D, Marchesi C (2009) Diagnosis, natural history, and management of Charcot–Marie–Tooth disease. Lancet Neurol 8(7):654–667. doi:10.1016/S1474-4422(09)70110-3
Viader A, Golden JP, Baloh RH, Schmidt RE, Hunter DA, Milbrandt J (2011) Schwann cell mitochondrial metabolism supports long-term axonal survival and peripheral nerve function. J Neurosci 31(28):10128–10140. doi:10.1523/JNEUROSCI.0884-11.2011
Fünfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, Brinkmann BG, Kassmann CM, Tzvetanova ID, Mobius W, Diaz F, Meijer D, Suter U, Hamprecht B, Sereda MW, Moraes CT, Frahm J, Goebbels S, Nave KA (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485(7399):517–521. doi:10.1038/nature11007
Viader A, Sasaki Y, Kim S, Strickland A, Workman CS, Yang K, Gross RW, Milbrandt J (2013) Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron 77(5):886–898. doi:10.1016/j.neuron.2013.01.012
Beirowski B, Babetto E, Golden JP, Chen YJ, Yang K, Gross RW, Patti GJ, Milbrandt J (2014) Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance. Nat Neurosci 17(10):1351–1361. doi:10.1038/nn.3809
Pooya S, Liu X, Kumar VB, Anderson J, Imai F, Zhang W, Ciraolo G, Ratner N, Setchell KD, Yoshida Y, Jankowski MP, Dasgupta B (2014) The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism. Nat Commun 5:4993. doi:10.1038/ncomms5993
Ino D, Sagara H, Suzuki J, Kanemaru K, Okubo Y, Iino M (2015) Neuronal regulation of Schwann cell mitochondrial Ca(2+) signaling during myelination. Cell Rep 12(12):1951–1959. doi:10.1016/j.celrep.2015.08.039
Pareyson D, Piscosquito G, Moroni I, Salsano E, Zeviani M (2013) Peripheral neuropathy in mitochondrial disorders. Lancet Neurol 12(10):1011–1024. doi:10.1016/S1474-4422(13)70158-3
Chu CC, Huang CC, Fang W, Chu NS, Pang CY, Wei YH (1997) Peripheral neuropathy in mitochondrial encephalomyopathies. Eur Neurol 37(2):110–115
Yiannikas C, McLeod JG, Pollard JD, Baverstock J (1986) Peripheral neuropathy associated with mitochondrial myopathy. Ann Neurol 20(2):249–257. doi:10.1002/ana.410200211
Santoro L, Carrozzo R, Malandrini A, Piemonte F, Patrono C, Villanova M, Tessa A, Palmeri S, Bertini E, Santorelli FM (2000) A novel SURF1 mutation results in Leigh syndrome with peripheral neuropathy caused by cytochrome c oxidase deficiency. Neuromuscul Disord 10(6):450–453
Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8(11):870–879. doi:10.1038/nrm2275
Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, Medicine Society TM (2009) A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol 11(6):414–430
Niemann A, Ruegg M, La Padula V, Schenone A, Suter U (2005) Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot–Marie–Tooth disease. J Cell Biol 170(7):1067–1078. doi:10.1083/jcb.200507087
Niemann A, Huber N, Wagner KM, Somandin C, Horn M, Lebrun-Julien F, Angst B, Pereira JA, Halfter H, Welzl H, Feltri ML, Wrabetz L, Young P, Wessig C, Toyka KV, Suter U (2014) The Gdap1 knockout mouse mechanistically links redox control to Charcot–Marie–Tooth disease. Brain 137(Pt 3):668–682. doi:10.1093/brain/awt371
Picard M, Shirihai OS, Gentil BJ, Burelle Y (2013) Mitochondrial morphology transitions and functions: implications for retrograde signaling? Am J Physiol Regul Integr Comp Physiol 304(6):R393–R406. doi:10.1152/ajpregu.00584.2012
Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11(12):872–884. doi:10.1038/nrm3013
Chowdhury SK, Smith DR, Fernyhough P (2013) The role of aberrant mitochondrial bioenergetics in diabetic neuropathy. Neurobiol Dis 51:56–65. doi:10.1016/j.nbd.2012.03.016
Chowdhury SK, Dobrowsky RT, Fernyhough P (2011) Nutrient excess and altered mitochondrial proteome and function contribute to neurodegeneration in diabetes. Mitochondrion 11(6):845–854. doi:10.1016/j.mito.2011.06.007
Kalichman MW, Powell HC, Mizisin AP (1998) Reactive, degenerative, and proliferative Schwann cell responses in experimental galactose and human diabetic neuropathy. Acta Neuropathol 95(1):47–56
Mizisin AP, Nelson RW, Sturges BK, Vernau KM, Lecouteur RA, Williams DC, Burgers ML, Shelton GD (2007) Comparable myelinated nerve pathology in feline and human diabetes mellitus. Acta Neuropathol 113(4):431–442. doi:10.1007/s00401-006-0163-8
Zhang L, Yu C, Vasquez FE, Galeva N, Onyango I, Swerdlow RH, Dobrowsky RT (2010) Hyperglycemia alters the schwann cell mitochondrial proteome and decreases coupled respiration in the absence of superoxide production. J Proteome Res 9(1):458–471. doi:10.1021/pr900818g
Vallianou N, Evangelopoulos A, Koutalas P (2009) Alpha-lipoic Acid and diabetic neuropathy. Rev Diabet Stud 6(4):230–236. doi:10.1900/RDS.2009.6.230
Pitceathly RD, Taanman JW, Rahman S, Meunier B, Sadowski M, Cirak S, Hargreaves I, Land JM, Nanji T, Polke JM, Woodward CE, Sweeney MG, Solanki S, Foley AR, Hurles ME, Stalker J, Blake J, Holton JL, Phadke R, Muntoni F, Reilly MM, Hanna MG, Consortium UK (2013) COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood. JAMA Neurol 70(12):1556–1561. doi:10.1001/jamaneurol.2013.3242
Diaz F, Thomas CK, Garcia S, Hernandez D, Moraes CT (2005) Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency. Hum Mol Genet 14(18):2737–2748. doi:10.1093/hmg/ddi307
Diaz F, Garcia S, Hernandez D, Regev A, Rebelo A, Oca-Cossio J, Moraes CT (2008) Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies. Gut 57(2):232–242. doi:10.1136/gut.2006.119180
Fukui H, Diaz F, Garcia S, Moraes CT (2007) Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 104(35):14163–14168. doi:10.1073/pnas.0705738104
Wang J, Wilhelmsson H, Graff C, Li H, Oldfors A, Rustin P, Bruning JC, Kahn CR, Clayton DA, Barsh GS, Thoren P, Larsson NG (1999) Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nat Genet 21(1):133–137. doi:10.1038/5089
Wredenberg A, Wibom R, Wilhelmsson H, Graff C, Wiener HH, Burden SJ, Oldfors A, Westerblad H, Larsson NG (2002) Increased mitochondrial mass in mitochondrial myopathy mice. Proc Natl Acad Sci USA 99(23):15066–15071. doi:10.1073/pnas.232591499
Silva JP, Kohler M, Graff C, Oldfors A, Magnuson MA, Berggren PO, Larsson NG (2000) Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nat Genet 26(3):336–340. doi:10.1038/81649
Sorensen L, Ekstrand M, Silva JP, Lindqvist E, Xu B, Rustin P, Olson L, Larsson NG (2001) Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. J Neurosci 21(20):8082–8090
Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11(3):619–633
Boneh A (2006) Regulation of mitochondrial oxidative phosphorylation by second messenger-mediated signal transduction mechanisms. Cell Mol Life Sci 63(11):1236–1248. doi:10.1007/s00018-005-5585-2
Shackelford DB, Shaw RJ (2009) The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9(8):563–575. doi:10.1038/nrc2676
Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13(4):251–262. doi:10.1038/nrm3311
Jaegle M, Ghazvini M, Mandemakers W, Piirsoo M, Driegen S, Levavasseur F, Raghoenath S, Grosveld F, Meijer D (2003) The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development. Genes Dev 17(11):1380–1391. doi:10.1101/gad.258203
Shen YA, Chen Y, Dao DQ, Mayoral SR, Wu L, Meijer D, Ullian EM, Chan JR, Lu QR (2014) Phosphorylation of LKB1/Par-4 establishes Schwann cell polarity to initiate and control myelin extent. Nat Commun 5:4991. doi:10.1038/ncomms5991
Chan JR, Jolicoeur C, Yamauchi J, Elliott J, Fawcett JP, Ng BK, Cayouette M (2006) The polarity protein Par-3 directly interacts with p75NTR to regulate myelination. Science 314(5800):832–836. doi:10.1126/science.1134069
Feltri ML, Graus Porta D, Previtali SC, Nodari A, Migliavacca B, Cassetti A, Littlewood-Evans A, Reichardt LF, Messing A, Quattrini A, Mueller U, Wrabetz L (2002) Conditional disruption of beta 1 integrin in Schwann cells impedes interactions with axons. J Cell Biol 156(1):199–209. doi:10.1083/jcb.200109021
Taveggia C, Feltri ML, Wrabetz L (2010) Signals to promote myelin formation and repair. Nat Rev Neurol 6(5):276–287. doi:10.1038/nrneurol.2010.37
Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13(9):566–578. doi:10.1038/nrm3412
Deluca HF, Engstrom GW (1961) Calcium uptake by rat kidney mitochondria. Proc Natl Acad Sci USA 47:1744–1750
Vasington FD, Murphy JV (1962) Ca ion uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation. J Biol Chem 237:2670–2677
McCormack JG, Denton RM (1979) The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex. Biochem J 180(3):533–544
McCormack JG, Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70(2):391–425
Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476(7360):341–345. doi:10.1038/nature10234
De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476(7360):336–340. doi:10.1038/nature10230
Hirose K, Kadowaki S, Tanabe M, Takeshima H, Iino M (1999) Spatiotemporal dynamics of inositol 1,4,5-trisphosphate that underlies complex Ca2+ mobilization patterns. Science 284(5419):1527–1530
Okubo Y, Kakizawa S, Hirose K, Iino M (2001) Visualization of IP(3) dynamics reveals a novel AMPA receptor-triggered IP(3) production pathway mediated by voltage-dependent Ca(2+) influx in Purkinje cells. Neuron 32(1):113–122
Okubo Y, Kakizawa S, Hirose K, Iino M (2004) Cross talk between metabotropic and ionotropic glutamate receptor-mediated signaling in parallel fiber-induced inositol 1,4,5-trisphosphate production in cerebellar Purkinje cells. J Neurosci 24(43):9513–9520. doi:10.1523/JNEUROSCI.1829-04.2004
Furutani K, Okubo Y, Kakizawa S, Iino M (2006) Postsynaptic inositol 1,4,5-trisphosphate signaling maintains presynaptic function of parallel fiber-Purkinje cell synapses via BDNF. Proc Natl Acad Sci USA 103(22):8528–8533. doi:10.1073/pnas.0600497103
Kanemaru K, Okubo Y, Hirose K, Iino M (2007) Regulation of neurite growth by spontaneous Ca2+ oscillations in astrocytes. J Neurosci 27(33):8957–8966. doi:10.1523/JNEUROSCI.2276-07.2007
Mashimo M, Okubo Y, Yamazawa T, Yamasaki M, Watanabe M, Murayama T, Iino M (2010) Inositol 1,4,5-trisphosphate signaling maintains the activity of glutamate uptake in Bergmann glia. Eur J Neurosci 32(10):1668–1677. doi:10.1111/j.1460-9568.2010.07452.x
Kanemaru K, Kubota J, Sekiya H, Hirose K, Okubo Y, Iino M (2013) Calcium-dependent N-cadherin up-regulation mediates reactive astrogliosis and neuroprotection after brain injury. Proc Natl Acad Sci USA 110(28):11612–11617. doi:10.1073/pnas.1300378110
Fields RD, Ni Y (2010) Nonsynaptic communication through ATP release from volume-activated anion channels in axons. Sci Signal 3(142):ra73. doi:10.1126/scisignal.2001128
Sabirov RZ, Okada Y (2009) The maxi-anion channel: a classical channel playing novel roles through an unidentified molecular entity. J Physiol Sci 59(1):3–21. doi:10.1007/s12576-008-0008-4
von Kugelgen I (2006) Pharmacological profiles of cloned mammalian P2Y-receptor subtypes. Pharmacol Ther 110(3):415–432. doi:10.1016/j.pharmthera.2005.08.014
Wildman SS, Unwin RJ, King BF (2003) Extended pharmacological profiles of rat P2Y2 and rat P2Y4 receptors and their sensitivity to extracellular H+ and Zn2+ ions. Br J Pharmacol 140(7):1177–1186. doi:10.1038/sj.bjp.0705544
Fitzgerald M (1987) Cutaneous primary afferent properties in the hind limb of the neonatal rat. J Physiol 383:79–92
Micu I, Jiang Q, Coderre E, Ridsdale A, Zhang L, Woulfe J, Yin X, Trapp BD, McRory JE, Rehak R, Zamponi GW, Wang W, Stys PK (2006) NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439(7079):988–992. doi:10.1038/nature04474
Hamilton NB, Kolodziejczyk K, Kougioumtzidou E, Attwell D (2016) Proton-gated Ca(2+)-permeable TRP channels damage myelin in conditions mimicking ischaemia. Nature 529(7587):523–527. doi:10.1038/nature16519
Garbay B, Heape AM, Sargueil F, Cassagne C (2000) Myelin synthesis in the peripheral nervous system. Prog Neurobiol 61(3):267–304
Harris JJ, Attwell D (2012) The energetics of CNS white matter. J Neurosci 32(1):356–371. doi:10.1523/JNEUROSCI.3430-11.2012
Chrast R, Saher G, Nave KA, Verheijen MH (2011) Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models. J Lipid Res 52(3):419–434. doi:10.1194/jlr.R009761
Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107(9):1058–1070. doi:10.1161/CIRCRESAHA.110.223545
Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795. doi:10.1038/nature05292
Vincent AM, Brownlee M, Russell JW (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci 959:368–383
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ino, D., Iino, M. Schwann cell mitochondria as key regulators in the development and maintenance of peripheral nerve axons. Cell. Mol. Life Sci. 74, 827–835 (2017). https://doi.org/10.1007/s00018-016-2364-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-016-2364-1