Abstract
G72 is a strong candidate susceptibility gene for schizophrenia and bipolar disorder, whose function remains enigmatic. Here we show that one splicing isoform of the gene (LG72) encodes for a mitochondrial protein. We also provide convergent lines of evidence that increase of endogenous or exogenous G72 levels promotes robust mitochondrial fragmentation in mammalian cell lines and primary neurons, which proceeds in a manner that does not depend on induction of apoptosis or alteration in mitochondrial transmembrane potential. Finally, we show that increase in G72 levels in immature primary neurons is accompanied by a marked increase in dendritic arborization. By contrast, we failed to confirm the originally proposed functional interaction between G72 and D-amino acid oxidase (DAO) in two tested cell lines. Our results suggest an alternative role for G72 in modulating mitochondrial function.
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References
Gogos JA, Gerber DJ . Schizophrenia susceptibility genes: emergence of positional candidates and future directions. Trends Pharmacol Sci 2006; 27: 226–233.
Detera-Wadleigh SD, McMahon FJ . G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. Biol Psychiatry 2006; 60: 106–114.
Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 2002; 99: 13675–13680.
Molla G, Bernasconi M, Sacchi S, Pilone MS, Pollegioni L . Expression in Escherichia coli and in vitro refolding of the human protein pLG72. Protein Expr Purif 2006; 46: 150–155.
Chen FC, Li WH . Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet 2001; 68: 444–456.
Britten R . Transposable elements have contributed to thousands of human proteins. Proc Natl Acad Sci USA 2006; 103: 1798–1803.
Hattori E, Liu C, Badner JA, Bonner TI, Christian SL, Maheshwari M et al. Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series. Am J Hum Genet 2003; 72: 1131–1140.
Mothet JP, Parent AT, Wolosker H, Brady Jr RO, Linden DJ, Ferris CD et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA 2000; 97: 4926–4931.
Coyle JT, Tsai G, Goff D . Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann NY Acad Sci 2003; 1003: 318–327.
Mukai J, Liu H, Burt RA, Swor DE, Lai WS, Karayiorgou M et al. Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nat Genet 2004; 36: 725–731.
Horiike K, Tojo H, Arai R, Nozaki M, Maeda T . -amino-acid oxidase is confined to the lower brain stem and cerebellum in rat brain: regional differentiation of astrocytes. Brain Res 1994; 652: 297–303.
Savelyeva L, Mamaeva S . Heterogeneity and balance of chromosomes in human cell line M-HeLa-76: analysis of 100 karyotypes. Cancer Genet Cytogenet 1987; 28: 311–325.
Ghosh S, Ghosh I . Variation of stemline karyotype in a HeLa cell line. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 1975; 84: 129–133.
Cherry SR, Biniszkiewicz D, van PL, Baltimore D, Jaenisch R . Retroviral expression in embryonic stem cells and hematopoietic stem cells. Mol Cell Biol 2000; 20: 7419–7426.
Pfanner N . Protein sorting: recognizing mitochondrial presequences. Curr Biol 2000; 10: R412–R415.
Okamoto K, Shaw JM . Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu Rev Genet 2005; 39: 503–536.
Niemann A, Ruegg M, La PV, Schenone A, Suter U . Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J Cell Biol 2005; 170: 1067–1078.
Stojanovski D, Koutsopoulos OS, Okamoto K, Ryan MT . Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J Cell Sci 2004; 117: 1201–1210.
Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM . A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol 1998; 143: 351–358.
Pitts KR, Yoon Y, Krueger EW, McNiven MA . The dynamin-like protein DLP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells. Mol Biol Cell 1999; 10: 4403–4417.
Tondera D, Czauderna F, Paulick K, Schwarzer R, Kaufmann J, Santel A . The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells. J Cell Sci 2005; 118: 3049–3059.
Legros F, Lombes A, Frachon P, Rojo M . Mitochondrial fusion in human cells is efficient, requires the inner membrane potential, and is mediated by mitofusins. Mol Biol Cell 2002; 13: 4343–4354.
Chen F, Cushion MT . Use of fluorescent probes to investigate the metabolic state of Pneumocystis carinii mitochondria. J Eukaryot Microbiol 1994; 41: 79S.
Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 2001; 1: 515–525.
James DI, Parone PA, Mattenberger Y, Martinou JC . hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem 2003; 278: 36373–36379.
Chang DT, Reynolds IJ . Differences in mitochondrial movement and morphology in young and mature primary cortical neurons in culture. Neuroscience 2006; 141: 727–736.
Arnold G, Liscum L, Holtzman E . Ultrastructural localization of D-amino acid oxidase in microperoxisomes of the rat nervous system. J Histochem Cytochem 1979; 27: 735–745.
Dabholkar AS . Ultrastructural localization of catalase and D-amino acid oxidase in ‘normal’ fetal mouse liver. Experientia 1986; 42: 144–147.
Hillman RT, Green RE, Brenner SE . An unappreciated role for RNA surveillance. Genome Biol 2004; 5: R8.
Yabuta N, Onda H, Watanabe M, Yoshioka N, Nagamori I, Funatsu T et al. Isolation and characterization of the TIGA genes, whose transcripts are induced by growth arrest. Nucleic Acids Res 2006; 34: 4878–4892.
Doan JW, Schmidt TR, Wildman DE, Uddin M, Goldberg A, Huttemann M et al. Coadaptive evolution in cytochrome c oxidase: 9 of 13 subunits show accelerated rates of nonsynonymous substitution in anthropoid primates. Mol Phylogenet Evol 2004; 33: 944–950.
Goldberg A, Wildman DE, Schmidt TR, Huttemann M, Goodman M, Weiss ML et al. Adaptive evolution of cytochrome c oxidase subunit VIII in anthropoid primates. Proc Natl Acad Sci USA 2003; 100: 5873–5878.
Oldham MC, Horvath S, Geschwind DH . Conservation and evolution of gene coexpression networks in human and chimpanzee brains. Proc Natl Acad Sci USA 2006; 103: 17973–17978.
Chen H, Chan DC . Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet 2005; 14 Spec No. 2: R283–R289.
Chen H, Chomyn A, Chan DC . Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 2005; 280: 26185–26192.
Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 2000; 26: 211–215.
Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 2004; 36: 449–451.
Li Z, Okamoto K, Hayashi Y, Sheng M . The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 2004; 119: 873–887.
Ziv NE, Smith SJ . Evidence for a role of dendritic filopodia in synaptogenesis and spine formation. Neuron 1996; 17: 91–102.
Chen H, Chan DC . Critical dependence of neurons on mitochondrial dynamics. Curr Opin Cell Biol 2006; 18: 453–459.
Ben-Shachar D . Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine. J Neurochem 2002; 83: 1241–1251.
Stork C, Renshaw PF . Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry 2005; 10: 900–919.
Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S . Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 2004; 61: 300–308.
Kasahara T, Kubota M, Miyauchi T, Noda Y, Mouri A, Nabeshima T et al. Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. Mol Psychiatry 2006; 11: 577–593.
Acknowledgements
We acknowledge A Garcia-Williams for technical support and M Paterlini for help in the beginning of the project. We thank M Sheng for the gift of Drp1-myc and the Drp1K38A-myc plasmids. This research was supported in part by the National Institutes of Health (grant MH67068) and by the New York Academy of Sciences (JAG). JAG is also the recipient of a McKnight Brain Disorders Award, an EJLB Scholar and a Vicente NARSAD Young Investigator.
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The authors declare they have no conflict of interests.
Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)
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Kvajo, M., Dhilla, A., Swor, D. et al. Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function. Mol Psychiatry 13, 685–696 (2008). https://doi.org/10.1038/sj.mp.4002052
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DOI: https://doi.org/10.1038/sj.mp.4002052
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