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Axonal Protein Synthesis and the Regulation of Local Mitochondrial Function

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Cell Biology of the Axon

Part of the book series: Results and Problems in Cell Differentiation ((RESULTS,volume 48))

Abstract

Axons and presynaptic nerve terminals of both invertebrate and mammalian SCG neurons contain a heterogeneous population of nuclear-encoded mitochondrial mRNAs and a local cytosolic protein synthetic system. Nearly one quarter of the total protein synthesized in these structural/functional domains of the neuron is destined for mitochondria. Acute inhibition of axonal protein synthesis markedly reduces the functional activity of mitochondria. The blockade of axonal protein into mitochondria had similar effects on the organelle’s functional activity. In addition to mitochondrial mRNAs, SCG axons contain approximately 200 different microRNAs (miRs), short, noncoding RNA molecules involved in the posttranscriptional regulation of gene expression. One of these miRs (miR-338) targets cytochrome c oxidase IV (COXIV) mRNA. This nuclear-encoded mRNA codes for a protein that plays a key role in the assembly of the mitochondrial enzyme complex IV and oxidative phosphorylation. Over-expression of miR-338 in the axon markedly decreases COXIV expression, mitochondrial functional activity, and the uptake of neurotransmitter into the axon. Conversely, the inhibition of endogeneous miR-338 levels in the axon significantly increased mitochondrial activity and norepinephrine uptake into the axon. The silencing of COXIV expression in the axon using short, inhibitory RNAs (siRNAs) yielded similar results, a finding that indicated that the effects of miR-338 on mitochondrial activity and axon function were mediated, at least in part, through local COXIV mRNA translation. Taken together, recent findings establish that proteins requisite for mitochondrial activity are synthesized locally in the axon and nerve terminal, and call attention to the intimacy of the relationship that has evolved between the distant cellular domains of the neuron and its energy generating systems.

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References

  • Amiri M, Hollenbeck PJ (2008) Mitochondrial biogenesis in the axons of vertebrate peripheral neurons. Dev Neurobiol 68:1348–1361

    Article  PubMed  CAS  Google Scholar 

  • Aschrafi A, Schwechter AD, Mameza MG, Natera-Naranjo O, Gioio AE, Kaplan BB (2008) MicroRNA-338 regulates local cytochrome c oxidase IV mRNA levels and oxidative phosphorylation in the axons of sympathetic neurons. J Neurosci 28:12581–12590

    Article  PubMed  CAS  Google Scholar 

  • Bauer MF, Hofman S (2006) Import of mitochondrial proteins. In: Shapira AHV (ed) Mitochondrial function and dysfunction. Academic, San Diego, CA, pp 57–90

    Google Scholar 

  • Beaumont V, Zhong N, Fletcher R, Froemke RC, Zucker RS (2001) Phosphorylation and local presynaptic protein synthesis in calcium- and calcineurin-dependent induction of crayfish long-term facilitation. Neuron 32:489–501

    Article  PubMed  CAS  Google Scholar 

  • Bleher R, Martin R (2001) Ribosomes in the squid giant axon. Neuroscience 107:527–534

    Article  PubMed  CAS  Google Scholar 

  • Brittis PA, Lu Q, Flanagan JG (2002) Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target. Cell 110:223–235

    Article  PubMed  CAS  Google Scholar 

  • Campbell DS, Holt CE (2001) Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32:1013–1026

    Article  PubMed  CAS  Google Scholar 

  • Campbell DS, Regan AG, Lopez JS, Tannahill D, Harris WA, Holt CE (2001) Semaphorin 3A elicits stage-dependent collapse, turning, and branching in Xenopus retinal growth cones. J Neurosci 21:8538–8547.

    PubMed  CAS  Google Scholar 

  • Campenot RN, Martin G (2001) Construction and use of compartmented cultures for studies of cell biology in neurons. In: Federoff S, Richardson A (eds) Protocols for neural cell culture. Humana, Totowa, NJ, pp 49–57

    Google Scholar 

  • Casadio A, Martin KC, Giustetto M, Zhu H, Chen M, Bartsch D, Bailey CH, Kandel ER (1999) A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99:221–237

    Article  PubMed  CAS  Google Scholar 

  • Chang DTW, Honick AS, Reynolds IJ (2006) Mitochondrial trafficking to synapses in cultured primary cortical neurons. J Neurosci 26:7035–7045

    Article  PubMed  CAS  Google Scholar 

  • Chun JT, Gioio AE, Crispino M, Giuditta A, Kaplan BB (1996) Differential compartmentalization of mRNAs in squid giant axon. J Neurochem 67:1806–1812

    Article  PubMed  CAS  Google Scholar 

  • Cox LJ, Hengst U, Gurskaya NG, Lukyanov KA, Jaffrey SR (2008) Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival. Nat Cell Biol 10:149–159

    Article  PubMed  CAS  Google Scholar 

  • Gioio AE, Eyman M, Zhang H, Lavina ZS, Giuditta A, Kaplan BB (2001) Local synthesis of nuclear-encoded mitochondrial proteins in the presynaptic nerve terminal. J Neurosci Res 64:447–453

    Article  PubMed  CAS  Google Scholar 

  • Gioio AE, Lavina ZS, Jurkovicova D, Zhang H, Eyman M, Giuditta A, Kaplan BB (2004) Nerve terminals of squid photoreceptor neurons contain a heterogeneous population of mRNAs and translate a transfected reporter mRNA. Eur J Neurosci 20:865–872

    Article  PubMed  Google Scholar 

  • Giuditta A et al (2009) Protein synthesis in nerve terminals and the glia-neuron unit. Results Probl Cell Differ doi: 10.1007/400_2009_9

    Google Scholar 

  • Giuditta A, Chun JT, Eyman M, Cefaliello C, Bruno AP, Crispino M (2008) Local gene expression in axons and nerve endings: the glia-neuron unit. Physiol Rev 88:515–555

    Article  PubMed  CAS  Google Scholar 

  • Hanz S, Perlson E, Willis D, Zheng JQ, Massarwa R, Huerta JJ, Koltzenburg M, Kohler M, van-Minnen J, Twiss JL, Fainzilber M (2003) Axoplasmic importins enable retrograde injury signaling in lesioned nerve. Neuron 40:1095–1104

    Article  PubMed  CAS  Google Scholar 

  • Heales SJR, Gegg ME, Clark JB (2006) Oxidative phosphorylation: structure, function, and Intermediary metabolism. In: Shapira AHV (ed) Mitochondrial function and dysfunction. Academic, San Diego, CA, pp 25–56

    Google Scholar 

  • Hengst U, Cox LJ, Macosko EZ, Jaffrey SR (2006) Functional and selective RNA interference in developing axons and growth cones. J Neurosci 26:5727–5732

    Article  PubMed  CAS  Google Scholar 

  • Hillefors M, Gioio AE, Mameza MG, Kaplan BB (2007) Axon viability and mitochondrial function are dependent on local protein synthesis in sympathetic neurons. Cell Mol Neurobiol 27:701–716

    Article  PubMed  CAS  Google Scholar 

  • Hollenbeck PJ, Saxton WM (2005) The axonal transport of mitochondria. J Cell Sci 118:5411–5419

    Article  PubMed  CAS  Google Scholar 

  • Hu JY, Meng X, Schacher S (2003) Redistribution of syntaxin mRNA in neuronal cell bodies regulates protein expression and transport during synapse formation and long-term synaptic plasticity. J Neurosci 23:1804–1815

    PubMed  CAS  Google Scholar 

  • Jimenez CR, Eyman M, Lavina ZS, Gioio A, Li KW, van der Schors RC, Geraerts WP, Giuditta A, Kaplan BB, van Minnen J (2002) Protein synthesis in synaptosomes: a proteomics analysis. J Neurochem 81:735–744

    Article  PubMed  CAS  Google Scholar 

  • Kosik KS (2006) The neuronal microRNA system. Nat Rev Neurosci 7:911–920

    Article  PubMed  CAS  Google Scholar 

  • Leung KM, van Horck FP, Lin AC, Allison R, Standart N, Holt CE (2006) Asymmetrical β-actin mRNA translation in growth cones mediates attractive turning to netrin-1. Nat Neurosci 9:1247–1256

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Park JS, Deng JH, Bai Y (2006) Cytochrome c oxidase subunit IV is essential for assembly and respiratory function of the enzyme complex. J Bioenerg Biomembr 38:283–291

    Article  PubMed  CAS  Google Scholar 

  • Li C, Sasaki Y, Takei K, Yamamoto H, Shouji M, Sugiyama Y, Kawakami T, Nakamura F, Yagi T, Ohshima T, Goshima Y (2004) Correlation between semaphorin3A-induced facilitation of axonal transport and local activation of a translation initiation factor eukaryotic translation initiation factor 4E. J Neurosci 24:6161–6170

    Article  PubMed  CAS  Google Scholar 

  • Liao L, Pilotte J, Xu T, Wong CCL, Edelman GM, Vanderklish P, Yates JR III (2007) BDNF induces widespread changes in synaptic protein content and up-regulates components of the translational machinery: an analysis using high-throughput proteomic. J Proteome Res 6:1059–1071

    Article  PubMed  CAS  Google Scholar 

  • Liu K, Hu JY, Wang D, Schacher S (2003) Protein synthesis at synapse versus cell body: enhanced but transient expression of long-term facilitation at isolated synapses. J Neurobiol 56:275–286

    Article  PubMed  CAS  Google Scholar 

  • Margeot A, Garcia M, Wang W, Tetaud E, di Rago JP, Jacq C (2005) Why are many mRNAs translated to the vicinity of mitochondria: a role in protein complex assembly? Gene 354:64–71

    Article  PubMed  CAS  Google Scholar 

  • Martin KC, Casadio A, Zhu H, Yaping E, Rose JC, Chen M, Bailey CH, Kandel ER (1997) Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91:927–938

    Article  PubMed  CAS  Google Scholar 

  • Ming GL, Wong ST, Henley J, Yuan XB, Song HJ, Spitzer NC, Poo MM (2002) Adaptation in the chemotactic guidance of nerve growth cones. Nature 417:411–418

    Article  PubMed  CAS  Google Scholar 

  • Moccia R, Chen D, Lyles V, Kapuya E, E Y, Kalachikov S, Spahn CM, Frank J, Kandel ER, Barad M, Martin KC (2003) An unbiased cDNA library prepared from isolated Aplysia sensory neuron processes is enriched for cytoskeletal and translational mRNAs. J Neurosci 23:9409–9417

    PubMed  CAS  Google Scholar 

  • Perrone Capano C, Giuditta A, Castigli E, Kaplan BB (1987) Occurrence and sequence complexity of polyadenylated RNA in squid axoplasm. J Neurochem 49:698–704

    Article  CAS  Google Scholar 

  • Schacher S, Wu F (2002) Synapse formation in the absence of cell bodies requires protein synthesis. J Neurosci 22:1831–1839

    PubMed  CAS  Google Scholar 

  • Si K, Giustetto M, Etkin A, Hsu R, Janisiewicz AM, Miniaci MC, Kim JH, Zhu H, Kandel ER (2003) A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in aplysia. Cell 115:893–904

    Article  PubMed  CAS  Google Scholar 

  • Verma P, Chierzi S, Codd AM, Campbell DS, Meyer RL, Holt CE, Fawcett JW (2005) Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. J Neurosci 25:331–342

    Article  PubMed  CAS  Google Scholar 

  • Wu KY, Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER, Jaffrey SR (2005) Local translation of RhoA regulates growth cone collapse. Nature 436:1020–1024

    Article  PubMed  CAS  Google Scholar 

  • Young JC, Obermann WM, Hartl FU (1998) Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90. J Biol Chem 273:18007–18010

    Article  PubMed  CAS  Google Scholar 

  • Young JC, Hoogenraad NJ, Hartl FU (2003) Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 112:41–50

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Poo MM (2002) Localized synaptic potentiation by BDNF requires local protein synthesis in the developing axon. Neuron 36:675–688

    Article  PubMed  CAS  Google Scholar 

  • Zheng JQ, Kellyc TK, Chang B, Ryazantsev S, Rajasekaran AK, Martin KC, Twiss JL (2001) A functional role for intra-axonal protein synthesis during axonal regeneration from adult sensory neurons. J Neurosci 21:9291–9303

    PubMed  CAS  Google Scholar 

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Acknowledgements

Work in the laboratory of B.B. Kaplan was supported by the Division of Intramural Research Programs of the National Institute of Mental Health. The expert technical assistance of Ms. Orlangie Natera-Naranjo is greatly appreciated.

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Authors and Affiliations

  1. Laboratory of Molecular Biology, National Institute of Mental Health, NIH, Bethesda, MD, 20892-1381, USA

    Barry B. Kaplan, Anthony E. Gioio, Mi Hillefors & Armaz Aschrafi

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  1. Barry B. Kaplan
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  2. Anthony E. Gioio
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  3. Mi Hillefors
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  4. Armaz Aschrafi
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Corresponding author

Correspondence to Barry B. Kaplan .

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Editors and Affiliations

  1. Summer Hill Lane 70, Williamsville, 14221, U.S.A.

    Edward Koenig

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© 2009 Springer-Verlag Berlin Heidelberg

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Kaplan, B.B., Gioio, A.E., Hillefors, M., Aschrafi, A. (2009). Axonal Protein Synthesis and the Regulation of Local Mitochondrial Function. In: Koenig, E. (eds) Cell Biology of the Axon. Results and Problems in Cell Differentiation, vol 48. Springer, Berlin, Heidelberg. https://doi.org/10.1007/400_2009_1

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