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Drosophila melanogaster homolog of Down syndrome critical region 1 is critical for mitochondrial function

Nature Neuroscience volume 8, pages 1577–1585 (2005)Cite this article

Abstract

Mitochondrial dysfunction has emerged as a common theme that underlies numerous neurological disorders, including Down syndrome. Down syndrome cultures and tissues show mitochondrial damage such as impaired mitochondrial enzyme activities, defective mitochondrial DNA repairs and accumulation of toxic free radicals, but the cause of mitochondrial dysfunction remains elusive. Here we demonstrate that the Drosophila melanogaster homolog of human Down syndrome critical region gene 1 (DSCR1), nebula (also known as sarah, sra), has a crucial role in the maintenance of mitochondrial function and integrity. We report that nebula protein is located in the mitochondria. An alteration in the abundance of nebula affects mitochondrial enzyme activities, mitochondrial DNA content, and the number and size of mitochondria. Furthermore, nebula interacts with the ADP/ATP translocator and influences its activity. These results identify nebula/DSCR1 as a regulator of mitochondrial function and integrity and further suggest that an increased level of DSCR1 may contribute to the mitochondrial dysfunction seen in Down syndrome.

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Figure 1: The nebula mutant flies show altered mitochondrial function.
Figure 2: The nebula mutants show a profound increase in the number of smaller mitochondria.
Figure 3: Nebula protein is found in the mitochondria and is mainly localized to the matrix adjacent to the inner mitochondrial membrane.
Figure 4: Nebula interacts with ANT.
Figure 5: Nebula and sesB interact in vivo.
Figure 6: Nebula regulates mitochondrial function independently of calcineurin.
Figure 7: Trisomy 21 fetal brain tissues show reduced mtDNA content.

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References

  1. Mattson, M.P. & Liu, D. Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders. Neuromolecular Med. 2, 215–231 (2002).

    Article  CAS  Google Scholar 

  2. Balaban, R.S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 120, 483–495 (2005).

    Article  CAS  Google Scholar 

  3. Wallace, D.C. Mitochondrial diseases in man and mouse. Science 283, 1482–1488 (1999).

    Article  CAS  Google Scholar 

  4. Arbuzova, S., Hutchin, T. & Cuckle, H. Mitochondrial dysfunction and Down's syndrome. Bioessays 24, 681–684 (2002).

    Article  Google Scholar 

  5. Busciglio, J. & Yankner, B.A. Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro. Nature 378, 776–779 (1995).

    Article  CAS  Google Scholar 

  6. Busciglio, J. et al. Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron 33, 677–688 (2002).

    Article  CAS  Google Scholar 

  7. Zeviani, M. & Carelli, V. Mitochondrial disorders. Curr. Opin. Neurol. 16, 585–594 (2003).

    Article  CAS  Google Scholar 

  8. Prince, J., Jia, S., Bave, U., Anneren, G. & Oreland, L. Mitochondrial enzyme deficiencies in Down's syndrome. J. Neural Transm. Park. Dis. Dement. Sect. 8, 171–181 (1994).

    Article  CAS  Google Scholar 

  9. Druzhyna, N., Nair, R.G., LeDoux, S.P. & Wilson, G.L. Defective repair of oxidative damage in mitochondrial DNA in Down's syndrome. Mutat. Res. 409, 81–89 (1998).

    Article  CAS  Google Scholar 

  10. Capone, G. et al. Evidence for increased mitochondrial superoxide production in Down syndrome. Life Sci. 70, 2885–2895 (2002).

    Article  CAS  Google Scholar 

  11. Fuentes, J.J. et al. A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum. Mol. Genet. 4, 1935–1944 (1995).

    Article  CAS  Google Scholar 

  12. Chang, K.T., Shi, Y.J. & Min, K.T. The Drosophila homolog of Down's syndrome critical region 1 gene regulates learning: implications for mental retardation. Proc. Natl. Acad. Sci. USA 100, 15794–15799 (2003).

    Article  CAS  Google Scholar 

  13. Fuentes, J.J. et al. DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways. Hum. Mol. Genet. 9, 1681–1690 (2000).

    Article  CAS  Google Scholar 

  14. Kingsbury, T.J. & Cunningham, K.W. A conserved family of calcineurin regulators. Genes Dev. 14, 1595–1604 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Rothermel, B. et al. A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling. J. Biol. Chem. 275, 8719–8725 (2000).

    Article  CAS  Google Scholar 

  16. Ryeom, S., Greenwald, R.J., Sharpe, A.H. & McKeon, F. The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin. Nat. Immunol. 4, 874–881 (2003).

    Article  CAS  Google Scholar 

  17. Ermak, G., Harris, C.D. & Davies, K.J. The DSCR1 (Adapt78) isoform 1 protein calcipressin 1 inhibits calcineurin and protects against acute calcium-mediated stress damage, including transient oxidative stress. FASEB J. 16, 814–824 (2002).

    Article  CAS  Google Scholar 

  18. Crawford, D.R. et al. Hamster adapt78 mRNA is a Down syndrome critical region homologue that is inducible by oxidative stress. Arch. Biochem. Biophys. 342, 6–12 (1997).

    Article  CAS  Google Scholar 

  19. Leahy, K.P. & Crawford, D.R. adapt78 protects cells against stress damage and suppresses cell growth. Arch. Biochem. Biophys. 379, 221–228 (2000).

    Article  CAS  Google Scholar 

  20. Lewis, D.L., Farr, C.L. & Kaguni, L.S. Drosophila melanogaster mitochondrial DNA: completion of the nucleotide sequence and evolutionary comparisons. Insect Mol. Biol. 4, 263–278 (1995).

    Article  CAS  Google Scholar 

  21. Pfister, S.C., Machado-Santelli, G.M., Han, S.W. & Henrique-Silva, F. Mutational analyses of the signals involved in the subcellular location of DSCR1. BMC Cell Biol. 3, 24 (2002).

    Article  Google Scholar 

  22. Genesca, L. et al. Phosphorylation of calcipressin 1 increases its ability to inhibit calcineurin and decreases calcipressin half-life. Biochem. J. 374, 567–575 (2003).

    Article  CAS  Google Scholar 

  23. Lin, H.Y. et al. Oxidative and calcium stress regulate DSCR1 (Adapt78/MCIP1) protein. Free Radic. Biol. Med. 35, 528–539 (2003).

    Article  CAS  Google Scholar 

  24. Hilioti, Z. et al. GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs. Genes Dev. 18, 35–47 (2004).

    Article  CAS  Google Scholar 

  25. Vega, R.B., Yang, J., Rothermel, B.A., Bassel-Duby, R. & Williams, R.S. Multiple domains of MCIP1 contribute to inhibition of calcineurin activity. J. Biol. Chem. 277, 30401–30407 (2002).

    Article  CAS  Google Scholar 

  26. Zhang, Y.Q. et al. stress sensitive B encodes an adenine nucleotide translocase in Drosophila melanogaster. Genetics 153, 891–903 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Klingenber, M. in The Enzymes of Biological Membranes (ed. Martonosi, A.N.) (Plenum, New York, 1985).

    Google Scholar 

  28. Homyk, T., Jr . Behavioral mutations of Drosophila melanogaster. II. Behavioral analysis and locus mapping. Genetics 87, 105–128 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Royden, C.S., Pirrotta, V. & Jan, L.Y. The tko locus, site of a behavioral mutation in D. melanogaster, codes for a protein homologous to prokaryotic ribosomal protein S12. Cell 51, 165–173 (1987).

    Article  CAS  Google Scholar 

  30. Sullivan, K.M. & Rubin, G.M. The Ca(2+)-calmodulin-activated protein phosphatase calcineurin negatively regulates EGF receptor signaling in Drosophila development. Genetics 161, 183–193 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Gajewski, K. et al. Requirement of the calcineurin subunit gene canB2 for indirect flight muscle formation in Drosophila. Proc. Natl. Acad. Sci. USA 100, 1040–1045 (2003).

    Article  CAS  Google Scholar 

  32. Graham, B.H. et al. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat. Genet. 16, 226–234 (1997).

    Article  CAS  Google Scholar 

  33. Esposito, L.A., Melov, S., Panov, A., Cottrell, B.A. & Wallace, D.C. Mitochondrial disease in mouse results in increased oxidative stress. Proc. Natl. Acad. Sci. USA 96, 4820–4825 (1999).

    Article  CAS  Google Scholar 

  34. Kaukonen, J. et al. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289, 782–785 (2000).

    Article  CAS  Google Scholar 

  35. Biousse, V., Pardue, M.T., Wallace, D.C. & Newman, N.J. The eyes of mito-mouse: mouse models of mitochondrial disease. J. Neuroophthalmol. 22, 279–285 (2002).

    Article  Google Scholar 

  36. Wallace, D.C. Mouse models for mitochondrial disease. Am. J. Med. Genet. 106, 71–93 (2001).

    Article  CAS  Google Scholar 

  37. St-Pierre, J., Buckingham, J.A., Roebuck, S.J. & Brand, M.D. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J. Biol. Chem. 277, 44784–44790 (2002).

    Article  CAS  Google Scholar 

  38. Strippoli, P., Lenzi, L., Petrini, M., Carinci, P. & Zannotti, M. A new gene family including DSCR1 (Down Syndrome Candidate Region 1) and ZAKI-4: characterization from yeast to human and identification of DSCR1-like 2, a novel human member (DSCR1L2). Genomics 64, 252–263 (2000).

    Article  CAS  Google Scholar 

  39. Hodson, D., Gatward, G. & Erber, W. Azurophilic granules in acute lymphoblastic leukaemia resulting from abundant mitochondria. Br. J. Haematol. 125, 265 (2004).

    Article  Google Scholar 

  40. Hirai, K. et al. Mitochondrial abnormalities in Alzheimer's disease. J. Neurosci. 21, 3017–3023 (2001).

    Article  CAS  Google Scholar 

  41. Wong-Riley, M. et al. Cytochrome oxidase in Alzheimer's disease: biochemical, histochemical, and immunohistochemical analyses of the visual and other systems. Vision Res. 37, 3593–3608 (1997).

    Article  CAS  Google Scholar 

  42. Roizen, N.J. & Patterson, D. Down's syndrome. Lancet 361, 1281–1289 (2003).

    Article  Google Scholar 

  43. Menendez, M. Down syndrome, Alzheimer's disease and seizures. Brain Dev. 27, 246–252 (2005).

    Article  Google Scholar 

  44. Ermak, G., Morgan, T.E. & Davies, K.J. Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease. J. Biol. Chem. 276, 38787–38794 (2001).

    Article  CAS  Google Scholar 

  45. Gardiner, K. et al. Report on the 'Expert workshop on the biology of chromosome 21: towards gene-phenotype correlations in Down syndrome', held June 11–14, 2004, Washington D.C. Cytogenet. Genome Res. 108, 269–77 (2005).

    Google Scholar 

  46. Cvejic, S., Zhu, Z., Felice, S.J., Berman, Y. & Huang, X.Y. The endogenous ligand Stunted of the GPCR Methuselah extends lifespan in Drosophila. Nat. Cell Biol. 6, 540–546 (2004).

    Article  CAS  Google Scholar 

  47. Tokuyasu, K.T. Immunochemistry on ultrathin frozen sections. Histochem. J. 12, 381–403 (1980).

    Article  CAS  Google Scholar 

  48. Wu, C.F., Suzuki, N. & Poo, M.M. Dissociated neurons from normal and mutant Drosophila larval central nervous system in cell culture. J. Neurosci. 3, 1888–1899 (1983).

    Article  CAS  Google Scholar 

  49. Duan, J. & Karmazyn, M. Relationship between oxidative phosphorylation and adenine nucleotide translocase activity of two populations of cardiac mitochondria and mechanical recovery of ischemic hearts following reperfusion. Can. J. Physiol. Pharmacol. 67, 704–709 (1989).

    Article  CAS  Google Scholar 

  50. Ganetzky, B. & Wu, C.F. Drosophila mutants with opposing effects on nerve excitability: genetic and spatial interactions in repetitive firing. J. Neurophysiol. 47, 501–514 (1982).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the EM Facility, Protein/Peptide Sequencing Facility and Light Imaging Facility at NINDS, NIH for assistance; EM Facility at Johns Hopkins University for help with immunogold electron microscopy; M. Ashburner for the sesB1 stock; R. Garesse for the ATPβ synthase antibody; the Brain and Tissue Bank at the University of Maryland, Baltimore, for fetal brain tissues; H. Nash and K. Fischbeck for critical reading of the manuscript; and Y. Shi for technical assistance. This work was supported by an intramural fund from NINDS, NIH, and funds from the March of Dimes Birth Defects Foundation to K.-T.M.

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  1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Karen T Chang & Kyung-Tai Min

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Correspondence to Kyung-Tai Min.

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Supplementary information

Supplementary Fig. 1

Specificity of the nebula antibody. (PDF 403 kb)

Supplementary Fig. 2

nebula mutants show a profound increase in the number of mitochondria. (PDF 778 kb)

Supplementary Fig. 3

Nebula is mainly found in the soluble mitochondrial fraction. (PDF 107 kb)

Supplementary Fig. 4

Summary of nebula function. (PDF 62 kb)

Supplementary Methods (PDF 68 kb)

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Chang, K., Min, KT. Drosophila melanogaster homolog of Down syndrome critical region 1 is critical for mitochondrial function. Nat Neurosci 8, 1577–1585 (2005). https://doi.org/10.1038/nn1564

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