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Syntaphilin Inactivation Can Enhance Axonal Mitochondrial Transport to Improve Spinal Cord Injury

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Abstract

Mitochondria are important organelle of eukaryotic cells. They consists of a large number of different proteins that provide most of the ATP and supply power for the growth, function, and regeneration of neurons. Therefore, smitochondrial transport ensures that adequate ATP is supplied for metabolic activities. Spinal cord injury (SCI), a detrimental condition, has high morbidity and mortality rates. Currently, the available treatments only provide symptomatic relief for long-term disabilities. Studies have implicated mitochondrial transport as a critical factor in axonal regeneration. Hence, enhancing mitochondrial transports could be beneficial for ameliorating SCI. Syntaphilin (Snph) is a mitochondrial docking protein that acts as a “static anchor,” and its inhibition enhances mitochondrial transports. Therefore, Snph as a key mediator of mitochondrial transports, may contribute to improving axonal regeneration following SCI. Herein, we examine Snph’s biological effects and its relation to mitochondrial pathway. Then, we elaborate on mitochondrial transports after SCI, the possible role of Snph in SCI, and some possible therapeutic approaches by Snph.

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References

  1. Jin LY, Li J, Wang KF, Xia WW, Zhu ZQ, Wang CR, Li XF, Liu HY (2021) Blood-spinal cord barrier in spinal cord injury: a review. J Neurotrauma 38(9):1203–1224. https://doi.org/10.1089/neu.2020.7413

    Article  PubMed  Google Scholar 

  2. Katoh H, Yokota K, Fehlings MG (2019) Regeneration of spinal cord connectivity through stem cell transplantation and biomaterial scaffolds. Front Cell Neurosci 13:248. https://doi.org/10.3389/fncel.2019.00248

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lu Q, Botchway BOA, Zhang Y, Jin T, Liu X (2022) SARM1 can be a potential therapeutic target for spinal cord injury. Cell Mol Life Sci 79(3):161. https://doi.org/10.1007/s00018-022-04195-4

    Article  CAS  PubMed  Google Scholar 

  4. Hayta E, Elden H (2018) Acute spinal cord injury: a review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention. J Chem Neuroanat 87:25–31. https://doi.org/10.1016/j.jchemneu.2017.08.001

    Article  CAS  PubMed  Google Scholar 

  5. Wang XJ, Peng CH, Zhang S, Xu XL, Shu GF, Qi J, Zhu YF, Xu DM et al (2019) Polysialic-acid-based micelles promote neural regeneration in spinal cord injury therapy. Nano Lett 19(2):829–838. https://doi.org/10.1021/acs.nanolett.8b04020

    Article  CAS  PubMed  Google Scholar 

  6. Allison DJ, Thomas A, Beaudry K, Ditor DS (2016) Targeting inflammation as a treatment modality for neuropathic pain in spinal cord injury: a randomized clinical trial. J Neuroinflammation 13(1):152. https://doi.org/10.1186/s12974-016-0625-4.PMID:27316678;PMCID:PMC4912827

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kawabata S, Takano M, Numasawa-Kuroiwa Y, Itakura G, Kobayashi Y, Nishiyama Y, Sugai K, Nishimura S et al (2016) Grafted human iPS cell-derived oligodendrocyte precursor cells contribute to robust remyelination of demyelinated axons after spinal cord injury. Stem Cell Reports 6(1):1–8. https://doi.org/10.1016/j.stemcr.2015.11.013

    Article  CAS  PubMed  Google Scholar 

  8. Xue F, Wu EJ, Zhang PX, Li-Ya A, Kou YH, Yin XF, Han N (2015) Biodegradable chitin conduit tubulation combined with bone marrow mesenchymal stem cell transplantation for treatment of spinal cord injury by reducing glial scar and cavity formation. Neural Regen Res 10(1):104–111. https://doi.org/10.4103/1673-5374.150715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ruschel J, Hellal F, Flynn KC, Dupraz S, Elliott DA, Tedeschi A, Bates M, Sliwinski C et al (2015) Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury. Science 348(6232):347–352. https://doi.org/10.1126/science.aaa2958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tse CM, Chisholm AE, Lam T, Eng JJ, SCIRE Research Team (2018) A systematic review of the effectiveness of task-specific rehabilitation interventions for improving independent sitting and standing function in spinal cord injury. J Spinal Cord Med 41(3):254–266. https://doi.org/10.1080/10790268.2017.1350340

    Article  PubMed  Google Scholar 

  11. Han Q, Xie Y, Ordaz JD, Huh AJ, Huang N, Wu W, Liu N, Chamberlain KA, et al. (2020) Restoring cellular energetics promotes axonal regeneration and functional recovery after spinal cord injury. Cell Metab. 31(3):623–641.e8. https://doi.org/10.1016/j.cmet.2020.02.002

  12. Petrova V, Nieuwenhuis B, Fawcett JW, Eva R (2021) Axonal organelles as molecular platforms for axon growth and regeneration after injury. Int J Mol Sci 22(4):1798. https://doi.org/10.3390/ijms22041798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. He Z, Jin Y (2016) Intrinsic control of axon regeneration. Neuron 90(3):437–451. https://doi.org/10.1016/j.neuron.2016.04.022

    Article  CAS  PubMed  Google Scholar 

  14. Petrova V, Eva R (2018) The virtuous cycle of axon growth: axonal transport of growth-promoting machinery as an intrinsic determinant of axon regeneration. Dev Neurobiol 78(10):898–925. https://doi.org/10.1002/dneu.22608

    Article  PubMed  Google Scholar 

  15. Scholpa NE, Schnellmann RG (2017) Mitochondrial-based therapeutics for the treatment of spinal cord injury: mitochondrial biogenesis as a potential pharmacological target. J Pharmacol Exp Ther 363(3):303–313. https://doi.org/10.1124/jpet.117.244806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhou B, Yu P, Lin MY, Sun T, Chen Y, Sheng ZH (2016) Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. J Cell Biol 214(1):103–119. https://doi.org/10.1083/jcb.201605101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Stefanatos R, Sanz A (2018) The role of mitochondrial ROS in the aging brain. FEBS Lett 592(5):743–758. https://doi.org/10.1002/1873-3468.12902

    Article  CAS  PubMed  Google Scholar 

  18. Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, Ji X, Lo EH (2016) Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535(7613):551–555. https://doi.org/10.1038/nature18928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lightowlers RN, Chrzanowska-Lightowlers ZM, Russell OM (2020) Mitochondrial transplantation-a possible therapeutic for mitochondrial dysfunction?: mitochondrial transfer is a potential cure for many diseases but proof of efficacy and safety is still lacking. EMBO Rep 21(9):e50964. https://doi.org/10.15252/embr.202050964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huang N, Li S, Xie Y, Han Q, Xu XM, Sheng ZH (2021) Reprogramming an energetic AKT-PAK5 axis boosts axon energy supply and facilitates neuron survival and regeneration after injury and ischemia. Curr Biol 31(14):3098-3114.e7. https://doi.org/10.1016/j.cub.2021.04.079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Miki A, Kanamori A, Nakamura M, Matsumoto Y, Mizokami J, Negi A (2014) The expression of syntaphilin is down-regulated in the optic nerve after axonal injury. Exp Eye Res 129:38–47. https://doi.org/10.1016/j.exer.2014.10.017

    Article  CAS  PubMed  Google Scholar 

  22. Hwang MJ, Bryant KG, Seo JH, Liu Q, Humphrey PA, Melnick MAC, Altieri DC, Robert ME (2019) Syntaphilin is a novel biphasic biomarker of aggressive prostate cancer and a metastasis predictor. Am J Pathol 189(6):1180–1189. https://doi.org/10.1016/j.ajpath.2019.02.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Seo JH, Agarwal E, Bryant KG, Caino MC, Kim ET, Kossenkov AV, Tang HY, Languino LR et al (2018) Syntaphilin ubiquitination regulates mitochondrial dynamics and tumor cell movements. Cancer Res 78(15):4215–4228. https://doi.org/10.1158/0008-5472.CAN-18-0595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen X, Xu W, Zhuo S, Chen X, Chen P, Guan S, Huang D, Sun X et al (2021) Syntaphilin downregulation facilitates radioresistance via mediating mitochondria distribution in esophageal squamous cell carcinoma. Free Radic Biol Med 165:348–359. https://doi.org/10.1016/j.freeradbiomed.2021.01.056

    Article  CAS  PubMed  Google Scholar 

  25. Lin MY, Cheng XT, Xie Y, Cai Q, Sheng ZH (2017) Removing dysfunctional mitochondria from axons independent of mitophagy under pathophysiological conditions. Autophagy 13(10):1792–1794. https://doi.org/10.1080/15548627.2017.1356552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Feng Y, Guo M, Zhao H, Han S, Hao Y, Yuan Y, Shen W, Sun J et al (2021) Dl-3-n-Butylphthalide alleviates demyelination and improves cognitive function by promoting mitochondrial dynamics in white matter lesions. Front Aging Neurosci 13:632374. https://doi.org/10.3389/fnagi.2021.632374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Caino MC, Seo JH, Aguinaldo A, Wait E, Bryant KG, Kossenkov AV, Hayden JE, Vaira V et al (2016) A neuronal network of mitochondrial dynamics regulates metastasis. Nat Commun 7:13730. https://doi.org/10.1038/ncomms13730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen YM, Gerwin C, Sheng ZH (2009) Dynein light chain LC8 regulates syntaphilin-mediated mitochondrial docking in axons. J Neurosci 29(30):9429–9438. https://doi.org/10.1523/JNEUROSCI.1472-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lao G, Scheuss V, Gerwin CM, Su Q, Mochida S, Rettig J, Sheng ZH (2000) Syntaphilin: a syntaxin-1 clamp that controls SNARE assembly. Neuron 25(1):191–201. https://doi.org/10.1016/s0896-6273(00)80882-x

    Article  CAS  PubMed  Google Scholar 

  30. Li S, Xiong GJ, Huang N, Sheng ZH (2020) The cross-talk of energy sensing and mitochondrial anchoring sustains synaptic efficacy by maintaining presynaptic metabolism. Nat Metab 2(10):1077–1095. https://doi.org/10.1038/s42255-020-00289-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cheng XT, Huang N, Sheng ZH (2022) Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration. Neuron 110(12):1899–1923. https://doi.org/10.1016/j.neuron.2022.03.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cheng XT, Sheng ZH (2021) Developmental regulation of microtubule-based trafficking and anchoring of axonal mitochondria in health and diseases. Dev Neurobiol 81(3):284–299. https://doi.org/10.1002/dneu.22748

    Article  PubMed  Google Scholar 

  33. Lin MY, Sheng ZH (2015) Regulation of mitochondrial transport in neurons. Exp Cell Res 334(1):35–44. https://doi.org/10.1016/j.yexcr.2015.01.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zheng Y, Zhang X, Wu X, Jiang L, Ahsan A, Ma S, Xiao Z, Han F et al (2019) Somatic autophagy of axonal mitochondria in ischemic neurons. J Cell Biol 218(6):1891–1907. https://doi.org/10.1083/jcb.201804101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shi X, Jiang X, Chen C, Zhang Y, Sun X (2022) The interconnections between the microtubules and mitochondrial networks in cardiocerebrovascular diseases: implications for therapy. Pharmacol Res 184:106452

    Article  CAS  PubMed  Google Scholar 

  36. Quintanilla RA, Tapia-Monsalves C, Vergara EH, Pérez MJ, Aranguiz A (2020) Truncated tau induces mitochondrial transport failure through the impairment of TRAK2 protein and bioenergetics decline in neuronal cells. Front Cell Neurosci 14:175. https://doi.org/10.3389/fncel.2020.00175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hirokawa N, Niwa S, Tanaka Y (2010) Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron 68(4):610–638. https://doi.org/10.1016/j.neuron.2010.09.039

    Article  CAS  PubMed  Google Scholar 

  38. Vale RD, Reese TS, Sheetz MP (1985) Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility. Cell 42(1):39–50. https://doi.org/10.1016/s0092-8674(85)80099-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Oeding SJ, Majstrowicz K, Hu XP, Schwarz V, Freitag A, Honnert U, Nikolaus P, Bähler M (2018) Identification of Miro1 and Miro2 as mitochondrial receptors for myosin XIX. J Cell Sci 131(17):jcs219469. https://doi.org/10.1242/jcs.219469

    Article  CAS  PubMed  Google Scholar 

  40. Mou Y, Dein J, Chen Z, Jagdale M, Li XJ (2021) MFN2 deficiency impairs mitochondrial transport and downregulates motor protein expression in human spinal motor neurons. Front Mol Neurosci 14:727552. https://doi.org/10.3389/fnmol.2021.727552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pekkurnaz G, Wang X (2022) Mitochondrial heterogeneity and homeostasis through the lens of a neuron. Nat Metab 4(7):802–812. https://doi.org/10.1038/s42255-022-00594-w

    Article  PubMed  Google Scholar 

  42. Vallee RB, McKenney RJ, Ori-McKenney KM (2012) Multiple modes of cytoplasmic dynein regulation. Nat Cell Biol 14(3):224–230. https://doi.org/10.1038/ncb2420

    Article  CAS  PubMed  Google Scholar 

  43. Canty JT, Yildiz A (2020) Activation and regulation of cytoplasmic dynein. Trends Biochem Sci 45(5):440–453. https://doi.org/10.1016/j.tibs.2020.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cason SE, Holzbaur ELF (2022) Selective motor activation in organelle transport along axons. Nat Rev Mol Cell Biol 23(11):699–714. https://doi.org/10.1038/s41580-022-00491-w

    Article  CAS  PubMed  Google Scholar 

  45. Kumar Sharma R, Chafik A, Bertolin G (2022) Mitochondrial transport, partitioning, and quality control at the heart of cell proliferation and fate acquisition. Am J Physiol Cell Physiol 322(2):C311–C325. https://doi.org/10.1152/ajpcell.00256.2021

    Article  CAS  PubMed  Google Scholar 

  46. López-Doménech G, Covill-Cooke C, Ivankovic D, Halff EF, Sheehan DF, Norkett R, Birsa N, Kittler JT (2018) Miro proteins coordinate microtubule- and actin-dependent mitochondrial transport and distribution. EMBO J 37(3):321–336. https://doi.org/10.15252/embj.201696380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Loss O, Stephenson FA (2017) Developmental changes in trak-mediated mitochondrial transport in neurons. Mol Cell Neurosci 80:134–147. https://doi.org/10.1016/j.mcn.2017.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Franker MA, Hoogenraad CC (2013) Microtubule-based transport - basic mechanisms, traffic rules and role in neurological pathogenesis. J Cell Sci 126(Pt 11):2319–2329. https://doi.org/10.1242/jcs.115030

    Article  CAS  PubMed  Google Scholar 

  49. Sheng ZH (2017) The interplay of axonal energy homeostasis and mitochondrial trafficking and anchoring. Trends Cell Biol 27(6):403–416. https://doi.org/10.1016/j.tcb.2017.01.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kruppa AJ, Buss F (2021) Motor proteins at the mitochondria-cytoskeleton interface. J Cell Sci 134(7):jcs226084. https://doi.org/10.1242/jcs.226084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Nguyen TT, Oh SS, Weaver D, Lewandowska A, Maxfield D, Schuler MH, Smith NK, Macfarlane J et al (2014) Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proc Natl Acad Sci U S A 111(35):E3631-3640. https://doi.org/10.1073/pnas.1402449111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Canty JT, Hensley A, Aslan M, Jack A, Yildiz A (2023) TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport. Nat Commun 14(1):1376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Smith GM, Gallo G (2018) The role of mitochondria in axon development and regeneration. Dev Neurobiol 78(3):221–237. https://doi.org/10.1002/dneu.22546

    Article  CAS  PubMed  Google Scholar 

  54. Verreet T, Weaver CJ, Hino H, Hibi M, Poulain FE (2019) Syntaphilin-mediated docking of mitochondria at the growth cone is dispensable for axon elongation in vivo. eNeuro 6(5):ENEURO.0026-19.2019

    Article  PubMed  PubMed Central  Google Scholar 

  55. Sainath R, Armijo-Weingart L, Ketscheck A, Xu Z, Li S, Gallo G (2017) Chondroitin sulfate proteoglycans negatively regulate the positioning of mitochondria and endoplasmic reticulum to distal axons. Dev Neurobiol 77(12):1351–1370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Li Q, Gao S (2017) Mitochondrial Dysfunction in Ischemic Stroke. In: Lapchak PA, Yang G-Y (eds) Translational research in stroke. Springer Singapore, Singapore, pp 201–221

    Chapter  Google Scholar 

  57. Yin W, Signore AP, Iwai M, Cao G, Gao Y, Chen J (2008) Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke 39(11):3057–3063. https://doi.org/10.1161/STROKEAHA.108.520114

    Article  PubMed  PubMed Central  Google Scholar 

  58. Rugarli EI, Langer T (2012) Mitochondrial quality control: a matter of life and death for neurons. EMBO J 31(6):1336–1349. https://doi.org/10.1038/emboj.2012.38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wang P, Shao BZ, Deng Z, Chen S, Yue Z, Miao CY (2018) Autophagy in ischemic stroke. Prog Neurobiol 163–164:98–117. https://doi.org/10.1016/j.pneurobio.2018.01.001

    Article  CAS  PubMed  Google Scholar 

  60. Lin MY, Cheng XT, Tammineni P, Xie Y, Zhou B, Cai Q, Sheng ZH (2017) Releasing syntaphilin removes stressed mitochondria from axons independent of mitophagy under pathophysiological conditions. Neuron 94(3):595-610.e6. https://doi.org/10.1016/j.neuron.2017.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Han SM, Baig HS, Hammarlund M (2016) Mitochondria localize to injured axons to support regeneration. Neuron 92(6):1308–1323. https://doi.org/10.1016/j.neuron.2016.11.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Guedes-Dias P, Holzbaur ELF (2019) Axonal transport: driving synaptic function. Science 366(6462):eaaw9997. https://doi.org/10.1126/science.aaw9997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen M, Li Y, Yang M, Chen X, Chen Y, Yang F, Lu S, Yao S et al (2016) A new method for quantifying mitochondrial axonal transport. Protein Cell 7(11):804–819. https://doi.org/10.1007/s13238-016-0268-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zheng YR, Zhang XN, Chen Z (2019) Mitochondrial transport serves as a mitochondrial quality control strategy in axons: implications for central nervous system disorders. CNS Neurosci Ther 25(7):876–886. https://doi.org/10.1111/cns.13122

    Article  PubMed  PubMed Central  Google Scholar 

  65. Chien L, Liang MZ, Chang CY, Wang C, Chen L (2018) Mitochondrial therapy promotes regeneration of injured hippocampal neurons. Biochim Biophys Acta Mol Basis Dis 1864(9 Pt B):3001–3012

    Article  CAS  PubMed  Google Scholar 

  66. Shi X, Zhao M, Fu C, Fu A (2017) Intravenous administration of mitochondria for treating experimental Parkinson’s disease. Mitochondrion 34:91–100

    Article  CAS  PubMed  Google Scholar 

  67. Gollihue JL, Patel SP, Eldahan KC, Cox DH, Donahue RR, Taylor BK, Sullivan PG, Rabchevsky AG (2018) Effects of mitochondrial transplantation on bioenergetics, cellular incorporation, and functional recovery after spinal cord injury. J Neurotrauma 35(15):1800–1818

    Article  PubMed  PubMed Central  Google Scholar 

  68. Chang JC, Chang HS, Wu YC, Cheng WL, Lin TT, Chang HJ, Kuo SJ, Chen ST et al (2019) Mitochondrial transplantation regulates antitumour activity, chemoresistance and mitochondrial dynamics in breast cancer. J Exp Clin Cancer Res 38(1):30

    Article  PubMed  PubMed Central  Google Scholar 

  69. Sun C, Liu X, Wang B, Wang Z, Liu Y, Di C, Si J, Li H et al (2019) Endocytosis-mediated mitochondrial transplantation: transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity. Theranostics 9(12):3595–3607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhang Z, Ma Z, Yan C, Pu K, Wu M, Bai J, Li Y, Wang Q (2019) Muscle-derived autologous mitochondrial transplantation: a novel strategy for treating cerebral ischemic injury. Behav Brain Res 356:322–331

    Article  CAS  PubMed  Google Scholar 

  71. Bi Y, Guo X, Zhang M, Zhu K, Shi C, Fan B, Wu Y, Yang Z et al (2021) Bone marrow derived-mesenchymal stem cell improves diabetes-associated fatty liver via mitochondria transformation in mice. Stem Cell Res Ther 12(1):602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Robicsek O, Ene HM, Karry R, Ytzhaki O, Asor E, McPhie D, Cohen BM, Ben-Yehuda R et al (2018) Isolated mitochondria transfer improves neuronal differentiation of schizophrenia-derived induced pluripotent stem cells and rescues deficits in a rat model of the disorder. Schizophr Bull 44(2):432–442

    Article  PubMed  Google Scholar 

  73. Anjum A, Yazid MD, Fauzi Daud M, Idris J, Ng AMH, Selvi Naicker A, Ismail OHR, Athi Kumar RK et al (2020) Spinal cord injury: pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci 21(20):7533. https://doi.org/10.3390/ijms21207533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Fischer T, Stern C, Freund P, Schubert M, Sutter R (2021) Wallerian degeneration in cervical spinal cord tracts is commonly seen in routine T2-weighted MRI after traumatic spinal cord injury and is associated with impairment in a retrospective study. Eur Radiol 31(5):2923–2932. https://doi.org/10.1007/s00330-020-07388-2

    Article  PubMed  Google Scholar 

  75. Zhang K, Jiang M, Fang Y (2021) The drama of Wallerian degeneration: the cast, crew, and script. Annu Rev Genet 55:93–113. https://doi.org/10.1146/annurev-genet-071819-103917

    Article  CAS  PubMed  Google Scholar 

  76. Koliatsos VE, Alexandris AS (2019) Wallerian degeneration as a therapeutic target in traumatic brain injury. Curr Opin Neurol 32(6):786–795. https://doi.org/10.1097/WCO.0000000000000763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bradshaw DV Jr, Knutsen AK, Korotcov A, Sullivan GM, Radomski KL, Dardzinski BJ, Zi X, McDaniel DP et al (2021) Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures. Acta Neuropathol Commun 9(1):89. https://doi.org/10.1186/s40478-021-01193-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Merlini E, Coleman MP, Loreto A (2022) Mitochondrial dysfunction as a trigger of programmed axon death. Trends Neurosci 45(1):53–63. https://doi.org/10.1016/j.tins.2021.10.014

    Article  CAS  PubMed  Google Scholar 

  79. Campbell G, Mahad DJ (2018) Mitochondrial dysfunction and axon degeneration in progressive multiple sclerosis. FEBS Lett 592(7):1113–1121. https://doi.org/10.1002/1873-3468.13013

    Article  CAS  PubMed  Google Scholar 

  80. Geden MJ, Deshmukh M (2016) Axon degeneration: context defines distinct pathways. Curr Opin Neurobiol 39:108–115. https://doi.org/10.1016/j.conb.2016.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wang B, Huang M, Shang D, Yan X, Zhao B, Zhang X (2021) Mitochondrial behavior in axon degeneration and regeneration. Front Aging Neurosci 13:650038. https://doi.org/10.3389/fnagi.2021.650038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rawson RL, Yam L, Weimer RM, Bend EG, Hartwieg E, Horvitz HR, Clark SG, Jorgensen EM (2014) Axons degenerate in the absence of mitochondria in C. elegans. Curr Biol 24(7):760–5. https://doi.org/10.1016/j.cub.2014.02.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Avery MA, Rooney TM, Pandya JD, Wishart TM, Gillingwater TH, Geddes JW, Sullivan PG, Freeman MR (2012) WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering. Curr Biol 22(7):596–600. https://doi.org/10.1016/j.cub.2012.02.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cartoni R, Norsworthy MW, Bei F, Wang C, Li S, Zhang Y, Gabel CV, Schwarz TL et al (2016) The mammalian-specific protein Armcx1 regulates mitochondrial transport during axon regeneration. Neuron 92(6):1294–1307. https://doi.org/10.1016/j.neuron.2016.10.060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kalinski AL, Kar AN, Craver J, Tosolini AP, Sleigh JN, Lee SJ, Hawthorne A, Brito-Vargas P et al (2019) Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition. J Cell Biol 218(6):1871–1890. https://doi.org/10.1083/jcb.201702187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Krauss R, Bosanac T, Devraj R, Engber T, Hughes RO (2020) Axons Matter: The promise of treating neurodegenerative disorders by targeting SARM1-mediated axonal degeneration. Trends Pharmacol Sci 41(4):281–293. https://doi.org/10.1016/j.tips.2020.01.006

    Article  CAS  PubMed  Google Scholar 

  87. O’Donnell KC, Vargas ME, Sagasti A (2013) WldS and PGC-1α regulate mitochondrial transport and oxidation state after axonal injury. J Neurosci 33(37):14778–14790. https://doi.org/10.1523/JNEUROSCI.1331-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cavallucci V, Bisicchia E, Cencioni MT, Ferri A, Latini L, Nobili A, Biamonte F, Nazio F et al (2014) Acute focal brain damage alters mitochondrial dynamics and autophagy in axotomized neurons. Cell Death Dis 5(11):e1545. https://doi.org/10.1038/cddis.2014.511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Slater PG, Domínguez-Romero ME, Villarreal M, Eisner V, Larraín J (2022) Mitochondrial function in spinal cord injury and regeneration. Cell Mol Life Sci 79(5):239. https://doi.org/10.1007/s00018-022-04261-x

    Article  CAS  PubMed  Google Scholar 

  90. Das S, Boczan J, Gerwin C, Zald PB, Sheng ZH (2003) Regional and developmental regulation of syntaphilin expression in the brain: a candidate molecular element of synaptic functional differentiation. Brain Res Mol Brain Res 116(1–2):38–49. https://doi.org/10.1016/s0169-328x(03)00212-2

    Article  CAS  PubMed  Google Scholar 

  91. Sun T, Qiao H, Pan PY, Chen Y, Sheng ZH (2013) Motile axonal mitochondria contribute to the variability of presynaptic strength. Cell Rep 4(3):413–419. https://doi.org/10.1016/j.celrep.2013.06.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Li YK, Zou J, Ye DM, Zeng Y, Chen CY, Luo GF, Zeng X (2020) Human p21-activated kinase 5 (PAK5) expression and potential mechanisms in relevant cancers: basic and clinical perspectives for molecular cancer therapeutics. Life Sci 241:117113. https://doi.org/10.1016/j.lfs.2019.117113

    Article  CAS  PubMed  Google Scholar 

  93. Li D, Pan Y, Huang Y, Zhang P, Fang X (2018) PAK5 induces EMT and promotes cell migration and invasion by activating the PI3K/AKT pathway in ovarian cancer. Anal Cell Pathol (Amst) 2018:8073124. https://doi.org/10.1155/2018/8073124

    Article  CAS  PubMed  Google Scholar 

  94. Han K, Zhou Y, Tseng KF, Hu H, Li K, Wang Y, Gan Z, Lin S et al (2018) PAK5 overexpression is associated with lung metastasis in osteosarcoma. Oncol Lett 15(2):2202–2210. https://doi.org/10.3892/ol.2017.7545

    Article  CAS  PubMed  Google Scholar 

  95. Manning BD, Toker A (2017) AKT/PKB signaling: navigating the network. Cell 169(3):381–405. https://doi.org/10.1016/j.cell.2017.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhao Y, Wang Q, Xie C, Cai Y, Chen X, Hou Y, He L, Li J et al (2021) Peptide ligands targeting FGF receptors promote recovery from dorsal root crush injury via AKT/mTOR signaling. Theranostics 11(20):10125–10147. https://doi.org/10.7150/thno.62525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yang L, Lei JF, Ouyang JY, Li MZ, Zhan Y, Feng XF, Lu Y, Li MC et al (2021) Effect of neurorepair for motor functional recovery enhanced by total saponins from Trillium tschonoskii maxim. Treatment in a rat model of focal ischemia. Front Pharmacol 12:763181. https://doi.org/10.3389/fphar.2021.763181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yao Z, Yuan W, Xu J, Tong W, Mi J, Ho PC, Chow DHK, Li Y et al (2022) Magnesium-encapsulated injectable hydrogel and 3D-engineered polycaprolactone conduit facilitate peripheral nerve regeneration. Adv Sci (Weinh) 9(21):e2202102. https://doi.org/10.1002/advs.202202102

    Article  CAS  PubMed  Google Scholar 

  99. Chen S, Owens GC, Crossin KL, Edelman DB (2007) Serotonin stimulates mitochondrial transport in hippocampal neurons. Mol Cell Neurosci 36(4):472–483. https://doi.org/10.1016/j.mcn.2007.08.004

    Article  CAS  PubMed  Google Scholar 

  100. Chen S, Owens GC, Edelman DB (2008) Dopamine inhibits mitochondrial motility in hippocampal neurons. PLoS One 3(7):e2804. https://doi.org/10.1371/journal.pone.0002804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Shaoxing University for infrastructure support.

Funding

Zhejiang Provincial Natural Science Foundation of China supported this study under grant no. LY19H170001.

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Author notes

  1. Qicheng Lu, Yong Zhang, and Benson O. A. Botchway contributed equally to this work.

Authors and Affiliations

  1. Department of Histology and Embryology, Medical College, Shaoxing University, Shaoxing, 312000, Zhejiang, China

    Qicheng Lu, Yong Zhang, Min Huang & Xuehong Liu

  2. Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China

    Benson O. A. Botchway

  3. Bupa Cromwell Hospital, London, UK

    Benson O. A. Botchway

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  1. Qicheng Lu
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  4. Min Huang
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All authors agreed to publish this article. XL designed the study. QL, YZ, BOAB, MH, and XL prepared the first draft of the manuscript. All authors revised the manuscript and approved the final article.

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Correspondence to Xuehong Liu.

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Lu, Q., Zhang, Y., Botchway, B.O.A. et al. Syntaphilin Inactivation Can Enhance Axonal Mitochondrial Transport to Improve Spinal Cord Injury. Mol Neurobiol 60, 6556–6565 (2023). https://doi.org/10.1007/s12035-023-03494-6

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