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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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.
The authors declare no competing financial interests.
Specificity of the nebula antibody. (PDF 403 kb)
nebula mutants show a profound increase in the number of mitochondria. (PDF 778 kb)
Nebula is mainly found in the soluble mitochondrial fraction. (PDF 107 kb)
Summary of nebula function. (PDF 62 kb)
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Chang, K., Min, K. 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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