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Evaluation of the Acquisition of the Aerobic Metabolic Capacity by Myelin, during its Development

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Abstract

Our previous reports indicate that the electron transfer chain and FoF1-ATP synthase are functionally expressed in myelin sheath, performing an extra-mitochondrial oxidative phosphorylation (OXPHOS), which would provide energy to the nerve axon. This supports the idea that myelin plays a trophic role for the axon. Although the four ETC complexes and ATP synthase are considered exquisite mitochondrial proteins, they are found ectopically expressed in several membranous structures. This study was designed to understand when and how the mitochondrial OXPHOS machinery is embedded in myelin, following myelinogenesis in the rat, which starts at birth and continues until the first month of age. Rats were sacrificed at different time points (from day 5 to 90 post birth). Western blot, immunofluorescence microscopy, luminometric, and oximetric analyses show that the isolated myelin starts to show OXPHOS components around the 11th day after birth and increases proportionally to the rat age, becoming similar to those of adult rat around the 30-third day. Interestingly, WB data show the same temporal relationship between myelinogenesis and appearance of proteins involved in mitochondrial fusion and cellular trafficking. It may be speculated that the OXPHOS complexes may be transferred to the endoplasmic reticulum membrane (known to interact with mitochondria) and from there through the Golgi apparatus to the forming myelin membrane.

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References

  1. Waxman SG (1977) Conduction in myelinated, unmyelinated, and demyelinated fibers. Arch Neurol 34:585–589

    Article  CAS  PubMed  Google Scholar 

  2. Morelli A, Ravera S, Panfoli I (2011) Hypothesis of an energetic function for myelin. Cell Biochem Biophys 61:179–187

    Article  CAS  PubMed  Google Scholar 

  3. Nave KA (2010) Myelination and the trophic support of long axons. Nat Rev Neurosci 11:275–283

    Article  CAS  PubMed  Google Scholar 

  4. Dutta R, Trapp BD (2010) Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol 93:1–12

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ravera S, Panfoli I, Calzia D, Aluigi MG, Bianchini P, Diaspro A, Mancardi G, Morelli A (2009) Evidence for aerobic ATP synthesis in isolated myelin vesicles. Int J Biochem Cell Biol 41:1581–1591

    Article  CAS  PubMed  Google Scholar 

  6. Ravera S, Panfoli I, Aluigi MG, Calzia D, Morelli A (2011) Characterization of Myelin Sheath F(o)F(1)-ATP synthase and its regulation by IF(1). Cell Biochem Biophys 59:63–70

    Article  CAS  PubMed  Google Scholar 

  7. Ravera S, Bartolucci M, Calzia D, Aluigi MG, Ramoino P, Morelli A, Panfoli I (2013) Tricarboxylic acid cycle-sustained oxidative phosphorylation in isolated myelin vesicles. Biochimie 95:1991–1998

    Article  CAS  PubMed  Google Scholar 

  8. Ravera S, Nobbio L, Visigalli D, Bartolucci M, Calzia D, Fiorese F, Mancardi G, Schenone A et al (2013) Oxydative phosphorylation in sciatic nerve myelin and its impairment in a model of dysmyelinating peripheral neuropathy. J Neurochem 126:82–92

    Article  CAS  PubMed  Google Scholar 

  9. Ravera S, Bartolucci M, Ramoino P, Calzia D, Traverso C, Panfoli I (2014) Oxydative metabolism in optic nerve myelin: new perspectives in hereditary optic neuropathies. Clin J Ophthalmol 1:003

    Google Scholar 

  10. Ravera S, Bartolucci M, Cuccarolo P, Litamè E, Illarcio M, Calzia D, Degan P, Morelli A et al (2015) Oxidative stress in myelin sheath: the other face of the extramitochondrial oxidative phosphorylation ability. Free Radic Res 49:1156–1164

    Article  CAS  PubMed  Google Scholar 

  11. Ravera S, Bartolucci M, Adriano E, Garbati P, Ferrando S, Ramoino P, Calzia D, Morelli A, et al (2015) Support of nerve conduction by respiring myelin sheath: role of connexons. Mol Neurobiol in press

  12. Silver I, Erecinska M (1998) Oxygen and ion concentrations in normoxic and hypoxic brain cells. Adv Exp Med Biol 454:7–16

    Article  CAS  PubMed  Google Scholar 

  13. Kann O, Kovacs R (2007) Mitochondria and neuronal activity. Am J Physiol Cell Physiol 292:C641–C657

    Article  CAS  PubMed  Google Scholar 

  14. Veltri KL, Espiritu M, Singh G (1990) Distinct genomic copy number in mitochondria of different mammalian organs. J Cell Physiol 143:160–164

    Article  CAS  PubMed  Google Scholar 

  15. Panfoli I, Bruschi M, Santucci L, Calzia D, Ravera S, Petretto A, Candiano G (2014) Myelin proteomics: the past, the unexpected and the future. Expert Rev Proteomics 11:345–354

    Article  CAS  PubMed  Google Scholar 

  16. Gat-Viks I, Geiger T, Barbi M, Raini G, Elroy-Stein O (2015) Proteomics-level analysis of myelin formation and regeneration in a mouse model for vanishing white matter disease. J Neurochem 134:513–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schoenfeld R, Wong A, Silva J, Li M, Itoh A, Horiuchi M, Itoh T, Pleasure D et al (2010) Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation. Mitochondrion 10:143–150

    Article  CAS  PubMed  Google Scholar 

  18. Haley JE, Samuels FG, Ledeen RW (1981) Study of myelin purity in relation to axonal contaminants. Cell Mol Neurobiol 1:175–187

    Article  CAS  PubMed  Google Scholar 

  19. Norton WT, Poduslo SE (1973) Myelination in rat brain: method of myelin isolation. J Neurochem 21:749–757

    Article  CAS  PubMed  Google Scholar 

  20. Lescuyer P, Strub J-M, Luche S, Diemer H, Martinez P, Van Dorsselaer A, Lunardi J, Rabilloud T (2003) Progress in the definition of a reference human mitochondrial proteome. Proteomics 3:157–167

    Article  CAS  PubMed  Google Scholar 

  21. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  22. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  23. Black JA, Foster RE, Waxman SG (1982) Rat optic nerve: freeze-fracture studies during development of myelinated axons. Brain Res 250:1–20

    Article  CAS  PubMed  Google Scholar 

  24. Lenaz G, Genova ML (2009) Structural and functional organization of the mitochondrial respiratory chain: a dynamic super-assembly. Int J Biochem Cell Biol 41:1750–1772

    Article  CAS  PubMed  Google Scholar 

  25. Lenaz G, Genova ML (2012) Supramolecular organisation of the mitochondrial respiratory chain: a new challenge for the mechanism and control of oxidative phosphorylation. Adv Exp Med Biol 748:107–144

    Article  CAS  PubMed  Google Scholar 

  26. Soltys BJ, Gupta RS (1999) Mitochondrial-matrix proteins at unexpected locations: are they exported? Trends Biochem Sci 24:174–177

    Article  CAS  PubMed  Google Scholar 

  27. Soltys BJ, Gupta RS (2000) Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from an evolutionary perspective. Int Rev Cytol 194:133–196

    Article  CAS  PubMed  Google Scholar 

  28. Crotty WJ, Ledbetter MC (1973) Membrane continuities involving chloroplasts and other organelles in plant cells. Science 182(80-):839–841

    Article  CAS  PubMed  Google Scholar 

  29. Wiedemann N, Meisinger C, Pfanner N (2009) Cell biology. Connecting organelles. Science 325:403–404

    Article  PubMed  Google Scholar 

  30. Giorgi C, De Stefani D, Bononi A, Rizzuto R, Pinton P (2009) Structural and functional link between the mitochondrial network and the endoplasmic reticulum. Int J Biochem Cell Biol 41:1817–1827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hroudová J, Fišar Z (2013) Control mechanisms in mitochondrial oxidative phosphorylation. Neural Regen Res 8:363–375

    PubMed  PubMed Central  Google Scholar 

  32. Claypool SM, Koehler CM (2012) The complexity of cardiolipin in health and disease. Trends Biochem Sci 37:32–41

    Article  CAS  PubMed  Google Scholar 

  33. Scherer SS, Arroyo EJ (2002) Recent progress on the molecular organization of myelinated axons. J Peripher Nerv Syst 7:1–12

    Article  CAS  PubMed  Google Scholar 

  34. Fern R, Davis P, Waxman SG, Ransom BR (1998) Axon conduction and survival in CNS white matter during energy deprivation: a developmental study. J Neurophysiol 79:95–105

    CAS  PubMed  Google Scholar 

  35. Anitei M, Pfeiffer SE (2006) Myelin biogenesis: sorting out protein trafficking. Curr Biol 16:R418–R421

    Article  CAS  PubMed  Google Scholar 

  36. Baron W, Hoekstra D (2010) On the biogenesis of myelin membranes: sorting, trafficking and cell polarity. FEBS Lett 584:1760–1770

    Article  CAS  PubMed  Google Scholar 

  37. White R, Krämer-Albers E-M (2014) Axon-glia interaction and membrane traffic in myelin formation. Front Cell Neurosci 7:284

    Article  PubMed  PubMed Central  Google Scholar 

  38. Trajkovic K, Dhaunchak AS, Goncalves JT, Wenzel D, Schneider A, Bunt G, Nave K-A, Simons M (2006) Neuron to glia signaling triggers myelin membrane exocytosis from endosomal storage sites. J Cell Biol 172:937–948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Monk KR, Voas MG, Franzini-Armstrong C, Hakkinen IS, Talbot WS (2013) Mutation of sec63 in zebrafish causes defects in myelinated axons and liver pathology. Dis Model Mech 6:135–145

    Article  PubMed  Google Scholar 

  40. Kovács GG, Höftberger R, Majtényi K, Horváth R, Barsi P, Komoly S, Lassmann H, Budka H et al (2005) Neuropathology of white matter disease in Leber’s hereditary optic neuropathy. Brain: J Neurol 128:35–41

    Article  Google Scholar 

  41. Niemann A, Berger P, Suter U (2006) Pathomechanisms of mutant proteins in Charcot-Marie-Tooth disease. Neuromolecular Med 8:217–242

    Article  CAS  PubMed  Google Scholar 

  42. Johnston PB, Gaster RN, Smith VC, Tripathi RC (1979) A clinicopathologic study of autosomal dominant optic atrophy. Am J Ophthalmol 88:868–875

    Article  CAS  PubMed  Google Scholar 

  43. 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 170:1067–1078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cortopassi G, Danielson S, Alemi M, Zhan SS, Tong W, Carelli V, Martinuzzi A, Marzuki S et al (2006) Mitochondrial disease activates transcripts of the unfolded protein response and cell cycle and inhibits vesicular secretion and oligodendrocyte-specific transcripts. Mitochondrion 6:161–175

    Article  CAS  PubMed  Google Scholar 

  45. Zambonin JL, Zhao C, Ohno N, Campbell GR, Engeham S, Ziabreva I, Schwarz N, Lee SE et al (2011) Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Brain: J Neurol 134:1901–1913

    Article  Google Scholar 

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Acknowledgements

This study was supported by a Grant from the “Fondazione Giuseppe Levi–Accademia Nazionale dei Lincei” for the research project entitled: “Produzione extra-mitocondriale di ATP in mielina: localizzazione dei complessi della catena respiratoria e possible ruolo nella degenerazione assonale in Sclerosi Multipla” and a Grant from the “Compagnia di San Paolo”-Neuroscience Program, for the research project entitled: “Energetic metabolism in myelinated axon: a new trophic role of myelin sheath”

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Authors and Affiliations

  1. Department of Pharmacy (DIFAR), Biochemistry Laboratory, University of Genova, Viale Benedetto XV 3, 16132, Genova, Italy

    Silvia Ravera, Martina Bartolucci, Daniela Calzia, Alessandro Morelli & Isabella Panfoli

  2. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Via de Toni 5, 16132, Genova, Italy

    Patrizia Garbati & Maurizio Balestrino

  3. DISTAV, University of Genova, C.so Europa 26, 16132, Genova, Italy

    Sara Ferrando & Paola Ramoino

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  1. Silvia Ravera
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Correspondence to Silvia Ravera.

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Ravera, S., Bartolucci, M., Garbati, P. et al. Evaluation of the Acquisition of the Aerobic Metabolic Capacity by Myelin, during its Development. Mol Neurobiol 53, 7048–7056 (2016). https://doi.org/10.1007/s12035-015-9575-6

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  • DOI: https://doi.org/10.1007/s12035-015-9575-6

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