Skip to main content
SpringerLink
Log in

Interactions between mitochondria and endoplasmic reticulum in demyelinated axons

  • Original Paper
  • Published:
Medical Molecular Morphology Aims and scope Submit manuscript

Abstract

Demyelination leads to axonal changes that involve the functions and dynamics of axonal mitochondria supporting metabolism and survival of axons. However, the changes in the physical interactions between mitochondria and endoplasmic reticulum, called mitochondria-associated membranes, are poorly understood in demyelinated axons. In this study, we investigated the three-dimensional ultrastructural changes in membrane juxtapositions between mitochondria and endoplasmic reticulum in axons of a chronic progressive demyelination mouse model caused by extra copies of proteolipid protein (PLP4e). In the optic nerve of PLP4e mice, most axons were ensheathed by myelin by age 1 month, but were demyelinated by age 5 months. At age 1 month, mitochondria in PLP4e mice were slightly larger than those in wild-type mice, while the size and frequency of juxtaposition were similar. At age 5 months, the sizes of mitochondria and size of juxtaposition in PLP4e mice were prominently larger than those in wild-type mice. In degenerating axons under demyelination, the enlargement of mitochondria was diminished, while the density and frequency of juxtaposition were similar to those of non-degenerating axons. These results suggest that interactions between mitochondria and ER are enhanced in chronically demyelinated axons and maintained during axonal degeneration in hereditary myelin diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468:244–252

    Article  CAS  PubMed  Google Scholar 

  2. Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 31:247–269

    Article  CAS  PubMed  Google Scholar 

  3. Lassmann H, Bruck W, Lucchinetti C (2001) Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 7:115–121

    Article  CAS  PubMed  Google Scholar 

  4. Waxman SG (2006) Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci 7:932–941

    Article  CAS  PubMed  Google Scholar 

  5. 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 30:6658–6666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mahad DH, Trapp BD, Lassmann H (2015) Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 14:183–193

    Article  CAS  PubMed  Google Scholar 

  7. Ohno N, Chiang H, Mahad DJ, Kidd GJ, Liu L, Ransohoff RM, Sheng ZH, Komuro H, Trapp BD (2014) Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons. Proc Natl Acad Sci USA 111:9953–9958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zambonin JL, Zhao C, Ohno N, Campbell GR, Engeham S, Ziabreva I, Schwarz N, Lee SE, Frischer JM, Turnbull DM, Trapp BD, Lassmann H, Franklin RJ, Mahad DJ (2011) Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Brain 134:1901–1913

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hoppins S, Lackner L, Nunnari J (2007) The machines that divide and fuse mitochondria. Annu Rev Biochem 76:751–780

    Article  CAS  PubMed  Google Scholar 

  10. Friedman JR, Nunnari J (2014) Mitochondrial form and function. Nature 505:335–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hayashi T, Rizzuto R, Hajnoczky G, Su TP (2009) MAM: more than just a housekeeper. Trends Cell Biol 19:81–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lamb CA, Yoshimori T, Tooze SA (2013) The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol 14:759–774

    Article  CAS  PubMed  Google Scholar 

  13. Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13:566–578

    Article  CAS  PubMed  Google Scholar 

  14. Theurey P, Rieusset J (2017) Mitochondria-associated membranes response to nutrient availability and role in metabolic diseases. Trends Endocrinol Metab 28:32–45

    Article  CAS  PubMed  Google Scholar 

  15. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610

    Article  CAS  PubMed  Google Scholar 

  16. Kornmann B, Currie E, Collins SR, Schuldiner M, Nunnari J, Weissman JS, Walter P (2009) An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science 325:477–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rowland AA, Voeltz GK (2012) Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat Rev Mol Cell Biol 13:607–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bernard-Marissal N, Medard JJ, Azzedine H, Chrast R (2015) Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration. Brain 138:875–890

    Article  PubMed  Google Scholar 

  19. van Vliet AR, Verfaillie T, Agostinis P (2014) New functions of mitochondria associated membranes in cellular signaling. Biochim Biophys Acta 1843:2253–2262

    Article  CAS  PubMed  Google Scholar 

  20. Yin X, Kidd GJ, Ohno N, Perkins GA, Ellisman MH, Bastian C, Brunet S, Baltan S, Trapp BD (2016) Proteolipid protein-deficient myelin promotes axonal mitochondrial dysfunction via altered metabolic coupling. J Cell Biol 215:531–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kagawa T, Ikenaka K, Inoue Y, Kuriyama S, Tsujii T, Nakao J, Nakajima K, Aruga J, Okano H, Mikoshiba K (1994) Glial cell degeneration and hypomyelination caused by overexpression of myelin proteolipid protein gene. Neuron 13:427–442

    Article  CAS  PubMed  Google Scholar 

  22. Thai TQ, Nguyen HB, Saitoh S, Wu B, Saitoh Y, Shimo S, Elewa YH, Ichii O, Kon Y, Takaki T, Joh K, Ohno N (2016) Rapid specimen preparation to improve the throughput of electron microscopic volume imaging for three-dimensional analyses of subcellular ultrastructures with serial block-face scanning electron microscopy. Med Mol Morphol 49:154–162

    Article  PubMed  Google Scholar 

  23. Cardona A, Saalfeld S, Schindelin J, Arganda-Carreras I, Preibisch S, Longair M, Tomancak P, Hartenstein V, Douglas RJ (2012) TrakEM2 software for neural circuit reconstruction. PLoS One 7:e38011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 31:7249–7258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nguyen HB, Sui Y, Thai TQ, Ikenaka K, Oda T, Ohno N (2018) Decreased number and increased volume with mitochondrial enlargement of cerebellar synaptic terminals in a mouse model of chronic demyelination. Med Mol Morphol 51:208–216

    Article  CAS  PubMed  Google Scholar 

  26. Marchi S, Patergnani S, Pinton P (2014) The endoplasmic reticulum-mitochondria connection: one touch, multiple functions. Biochim Biophys Acta 1837:461–469

    Article  CAS  PubMed  Google Scholar 

  27. Filadi R, Greotti E, Turacchio G, Luini A, Pozzan T, Pizzo P (2015) Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling. Proc Natl Acad Sci USA 112:E2174–E2181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Leal NS, Schreiner B, Pinho CM, Filadi R, Wiehager B, Karlstrom H, Pizzo P, Ankarcrona M (2016) Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid beta-peptide production. J Cell Mol Med 20:1686–1695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. de Brito OM, Scorrano L (2010) An intimate liaison: spatial organization of the endoplasmic reticulum-mitochondria relationship. EMBO J 29:2715–2723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Inoue K (2005) PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 6:1–16

    Article  CAS  PubMed  Google Scholar 

  31. Willard HF, Riordan JR (1985) Assignment of the gene for myelin proteolipid protein to the X chromosome: implications for X-linked myelin disorders. Science 230:940–942

    Article  CAS  PubMed  Google Scholar 

  32. Readhead C, Schneider A, Griffiths I, Nave K-A (1994) Premature arrest of myelin formation in transgenic mice with increased proteolipid protein gene dosage. Neuron 12:583–595

    Article  CAS  PubMed  Google Scholar 

  33. Mahad DJ, Ziabreva I, Campbell G, Lax N, White K, Hanson PS, Lassmann H, Turnbull DM (2009) Mitochondrial changes within axons in multiple sclerosis. Brain 132:1161–1174

    Article  PubMed  Google Scholar 

  34. Mutsaers SE, Carroll WM (1998) Focal accumulation of intra-axonal mitochondria in demyelination of the cat optic nerve. Acta Neuropathol 96:139–143

    Article  CAS  PubMed  Google Scholar 

  35. Sathornsumetee S, McGavern DB, Ure DR, Rodriguez M (2000) Quantitative ultrastructural analysis of a single spinal cord demyelinated lesion predicts total lesion load, axonal loss, and neurological dysfunction in a murine model of multiple sclerosis. Am J Pathol 157:1365–1376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Witte ME, Bo L, Rodenburg RJ, Belien JA, Musters R, Hazes T, Wintjes LT, Smeitink JA, Geurts JJ, De Vries HE, van der Valk P, van Horssen J (2009) Enhanced number and activity of mitochondria in multiple sclerosis lesions. J Pathol 219:193–204

    Article  PubMed  Google Scholar 

  37. Naon D, Zaninello M, Giacomello M, Varanita T, Grespi F, Lakshminaranayan S, Serafini A, Semenzato M, Herkenne S, Hernandez-Alvarez MI, Zorzano A, De Stefani D, Dorn GW, Scorrano L (2016) Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc Natl Acad Sci USA 113:11249–11254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Szymanski J, Janikiewicz J, Michalska B, Patalas-Krawczyk P, Perrone M, Ziolkowski W, Duszynski J, Pinton P, Dobrzyn A, Wieckowski MR (2017) Interaction of mitochondria with the endoplasmic reticulum and plasma membrane in calcium homeostasis, lipid trafficking and mitochondrial structure. Int J Mol Sci 18:1576

    Article  CAS  PubMed Central  Google Scholar 

  39. Campbell G, Mahad DJ (2018) Mitochondrial dysfunction and axon degeneration in progressive multiple sclerosis. FEBS Lett 592:1113–1121

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is partly supported by JSPS KAKENHI Grant Number 16K18977 (to N.O.), Cooperative Research Program of “Network Joint Research Center for Materials and Devices”, Research Grant from National Center of Neurology and Psychiatry (No. 30-5 to N.O.) and Cooperative Study Programs of National Institute for Physiological Sciences (to N.O.). We would like to thank Setsuro Fujii Memorial, Osaka Foundation for Promotion of Fundamental Medical Research, for providing the support.

Author information

Authors and Affiliations

  1. Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan

    Truc Quynh Thai, Huy Bang Nguyen, Yang Sui, Kazuhiro Ikenaka & Nobuhiko Ohno

  2. Departments of Anatomy and Structural Biology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan

    Truc Quynh Thai, Huy Bang Nguyen, Yang Sui & Toshiyuki Oda

  3. Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan

    Nobuhiko Ohno

Authors
  1. Truc Quynh Thai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huy Bang Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Sui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuhiro Ikenaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshiyuki Oda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobuhiko Ohno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nobuhiko Ohno.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thai, T.Q., Nguyen, H.B., Sui, Y. et al. Interactions between mitochondria and endoplasmic reticulum in demyelinated axons. Med Mol Morphol 52, 135–146 (2019). https://doi.org/10.1007/s00795-018-0212-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00795-018-0212-0

Keywords

Search

Navigation