Advertisement

NeuroMolecular Medicine

, Volume 21, Issue 3, pp 314–321 | Cite as

Sideroflexin 3 is a Mitochondrial Protein Enriched in Neurons

  • Aileen Rivell
  • Ronald S. Petralia
  • Ya-Xian Wang
  • Mark P. Mattson
  • Pamela J. YaoEmail author
Original Paper

Abstract

Sideroflexin 1 (Sfxn1) is a mitochondrial serine transporter involved in one-carbon metabolism in blood and cancer cell lines. The expression of other Sfxn homologs varies across tissues implying that each homolog may have tissue-specific functions. RNA databases suggest that among the Sfxns, Sfxn3 may have a specific function in the brain. Here, we systematically analyzed the level, cellular distribution, and subcellular localization of Sfxn3 protein in the developing and adult rodent brain. We found that, in the cortex and hippocampus, Sfxn3 protein level is low at birth but increases during development and remains at a high level in the mature brains. Similarly, in cultured hippocampal neurons, Sfxn3 protein level is low in young neurons but increases as neurons mature. Sfxn3 protein level is much higher in neurons than in astrocytes. Within neurons, Sfxn3 localizes to mitochondria in all major neuronal compartments. Our results establish that Sfxn3 is a mitochondrial protein enriched in neurons wherein it is developmentally expressed. These findings provide a foundation for future research aimed at understanding the functions of Sfxn3 and one-carbon metabolism in neurons.

Keywords

Sideroflexin Mitochondria Brain Neuron One-carbon metabolism 

Notes

Acknowledgements

We thank Dr. Fred E. Indig for assistance in confocal Airyscan imaging. We thank Drs. Lin Lin and Dax Hoffman for mouse tissue for immunogold labeling. This study was supported by the Intramural Research Programs of the National Institutes of Health, National Institute on Aging; and the National Institutes of Health, National Institute on Deafness and Other Communication Disorders. The Advanced Imaging Core code is ZIC DC000081.

Supplementary material

12017_2019_8553_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 18 kb)
12017_2019_8553_MOESM2_ESM.jpg (736 kb)
Supplementary material 2 (JPEG 735 kb)
12017_2019_8553_MOESM3_ESM.jpg (2.1 mb)
Supplementary material 3 (JPEG 2194 kb)
12017_2019_8553_MOESM4_ESM.jpg (3.5 mb)
Supplementary material 4 (JPEG 3626 kb)

References

  1. Amorim, I. S., Graham, L. C., Carter, R. N., Morton, N. M., Hammachi, F., Kunath, T., et al. (2017). Sideroflexin 3 is an α-synuclein-dependent mitochondrial protein that regulates synaptic morphology. Journal of Cell Science, 130, 325–331.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Cahoy, J. D., Emery, B., Kaushal, A., Foo, L. C., Zamanian, J. L., Christopherson, K. S., et al. (2008). A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource for understanding brain development and function. Journal of Neuroscience, 28, 264–278.CrossRefPubMedGoogle Scholar
  3. Dotti, C. G., Sullivan, C. A., & Banker, G. A. (1998). The establishment of polarity by hippocampal neurons in culture. Journal of Neuroscience, 8, 1454–1468.CrossRefGoogle Scholar
  4. Ducker, G. S., & Rabinowitz, J. D. (2017). One-Carbon Metabolism in Health and Disease. Cell Metabolism, 25, 27–42.CrossRefPubMedGoogle Scholar
  5. Endo, T., & Kohda, D. (2002). Functions of outer membrane receptors in mitochondrial protein import. Biochimica et Biophysica Acta, 1592, 3–14.CrossRefPubMedGoogle Scholar
  6. Goslin, K., & Banker, G. (1989). Experimental observations on the development of polarity by hippocampal neurons in culture. Journal of Cell Biology, 108, 1507–1516.CrossRefPubMedGoogle Scholar
  7. Kaech, S., & Banker, G. (2006). Culturing hippocampal neurons. Nature Protocols, 1, 2406–2415.CrossRefPubMedGoogle Scholar
  8. Kory, N., Wyant, G. A., Prakash, G., de Bos, J., Bottanelli, F., Pacold, M. E., et al. (2018). SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. Science, 362, 6416.CrossRefGoogle Scholar
  9. Labuschagne, C. F., van den Broek, N. J., Mackay, G. M., Vousden, K. H., & Maddocks, O. D. (2014). Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep., 7, 1248–1258.CrossRefPubMedGoogle Scholar
  10. Li, X., Han, D., Kin Ting Kam, R., Guo, X., Chen, M., Yang, Y., et al. (2010). Developmental expression of sideroflexin family genes in Xenopus embryos. Developmental Dynamics, 239, 2742–2747.CrossRefPubMedGoogle Scholar
  11. Lockhart, P. J., Holtom, B., Lincoln, S., Husseym, J., Zimprich, A., Gasser, T., et al. (2002). The human sideroflexin 5 (SFXN5) gene: Sequence, expression analysis and exclusion as a candidate for PARK3. Gene, 285, 229–237.CrossRefPubMedGoogle Scholar
  12. Mattson, M. P., Dou, P., & Kater, S. B. (1988). Outgrowth-regulating actions of glutamate in isolated hippocampal pyramidal neurons. Journal of Neuroscience, 8, 2087–2100.CrossRefPubMedGoogle Scholar
  13. Mattson, M. P., Murrain, M., Guthrie, P. B., & Kater, S. B. (1989). Fibroblast growth factor and glutamate: Opposing roles in the generation and degeneration of hippocampal neuroarchitecture. Journal of Neuroscience, 9, 3728–3740.CrossRefPubMedGoogle Scholar
  14. Minjarez, B., Calderón-González, K. G., Rustarazo, M. L., Herrera-Aguirre, M. E., Labra-Barrios, M. L., Rincon-Limas, D. E., et al. (2016). Identification of proteins that are differentially expressed in brains with Alzheimer’s disease using iTRAQ labeling and tandem mass spectrometry. Journal of Proteomics, 139, 103–121.CrossRefPubMedGoogle Scholar
  15. Pagliarini, D. J., Calvo, S. E., Chang, B., Sheth, S. A., Vafai, S. B., Ong, S. E., et al. (2008). A mitochondrial protein compendium elucidates complex I disease biology. Cell, 134, 112–123.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Petralia, R. S., Wang, Y. X., Hua, F., Yi, Z., Zhou, A., Ge, L., et al. (2010). Organization of NMDA receptors at extrasynaptic locations. Neuroscience, 167, 68–87.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Petralia, R. S., & Wenthold, R. J. (1999). Immunocytochemistry of NMDA receptors. Methods in Molecular Biology, 128, 73–92.PubMedGoogle Scholar
  18. Rivell, A., Petralia, R. S., Wang, Y. X., Clawson, E., Moehl, K., Mattson, M. P., et al. (2019). Sonic hedgehog expression in the postnatal brain. Biology Open.  https://doi.org/10.1242/bio.040592.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Sun, W., Maffie, J. K., Lin, L., Petralia, R. S., Rudy, B., & Hoffman, D. A. (2011). DPP6 establishes the A-type K(+) current gradient critical for the regulation of dendritic excitability in CA1 hippocampal neurons. Neuron, 71, 1102–1115.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Tushev, G., Glock, C., Heumüller, M., Biever, A., Jovanovic, M., & Schuman, E. M. (2018). Alternative 3′ UTRs modify the localization, regulatory potential, stability, and plasticity of mrnas in neuronal compartments. Neuron, 98, 495–511.CrossRefPubMedGoogle Scholar
  21. Yang, M., & Vousden, K. H. (2016). Serine and one-carbon metabolism in cancer. Nature Reviews Cancer, 16, 650–662.CrossRefPubMedGoogle Scholar
  22. Yao, P. J., Manor, U., Petralia, R. S., Brose, R. D., Wu, R. T., Ott, C., et al. (2017). Sonic hedgehog pathway activation increases mitochondrial abundance and activity in hippocampal neurons. Molecular Biology of the Cell, 28, 387–439.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Yao, P. J., Petralia, R. S., Ott, C., Wang, Y. X., Lippincott-Schwartz, J., & Mattson, M. P. (2015). Dendrosomatic sonic hedgehog signaling in hippocampal neurons regulates axon elongation. Journal of Neuroscience, 35, 16126–16141.CrossRefPubMedGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Laboratory of NeurosciencesNIA/NIH Biomedical Research CenterBaltimoreUSA
  2. 2.Advanced Imaging CoreNIDCD/NIHBethesdaUSA

Personalised recommendations