The Armc10/SVH gene: genome context, regulation of mitochondrial dynamics and protection against Aβ-induced mitochondrial fragmentation.
Mitochondrial function and dynamics are essential for neurotransmission, neural function and neuronal viability. Recently, we showed that the eutherian-specific Armcx gene cluster (Armcx1-6 genes), located in the X chromosome, encodes for a new family of proteins that localise to mitochondria, regulating mitochondrial trafficking. The Armcx gene cluster evolved by retrotransposition of the Armc10 gene mRNA, which is present in all vertebrates and is considered to be the ancestor gene. Here we investigate the genomic organisation, mitochondrial functions and putative neuroprotective role of the Armc10 ancestor gene. The genomic context of the Armc10 locus shows considerable syntenic conservation among vertebrates, and sequence comparisons and CHIP-data suggest the presence of at least three conserved enhancers. We also show that the Armc10 protein localises to mitochondria and that it is highly expressed in the brain. Furthermore, we show that Armc10 levels regulate mitochondrial trafficking in neurons, but not mitochondrial aggregation, by controlling the number of moving mitochondria. We further demonstrate that the Armc10 protein interacts with the KIF5/Miro1-2/Trak2 trafficking complex. Finally, we show that overexpression of Armc10 in neurons prevents Aβ-induced mitochondrial fission and neuronal death. Our data suggest both conserved and differential roles of the Armc10/Armcx gene family in regulating mitochondrial dynamics in neurons, and underscore a protective effect of the Armc10 gene against Aβ-induced toxicity. Overall, our findings support a further degree of regulation of mitochondrial dynamics in the brain of more evolved mammals.
1] Department of Cell Biology, University of Barcelona, Barcelona E-08028, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona E-08028, Spain.
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Serrat
1] Department of Cell Biology, University of Barcelona, Barcelona E-08028, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona E-08028, Spain.
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Mirra
1] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona E-08028, Spain [2] Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, CSIC, IDIBAPS, Barcelona E-08036, Spain.
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Figueiro-Silva
Department of Genetics, University of Barcelona, Barcelona E-08028, Spain.
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Navas-Pérez
1] Department of Cell Biology, University of Barcelona, Barcelona E-08028, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona E-08028, Spain.
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Quevedo
1] Department of Cell Biology, University of Barcelona, Barcelona E-08028, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona E-08028, Spain.
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López-Doménech
1] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona E-08028, Spain [2] Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, CSIC, IDIBAPS, Barcelona E-08036, Spain.
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Podlesniy
1] Department of Cell Biology, University of Barcelona, Barcelona E-08028, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona E-08028, Spain.
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Ulloa
Department of Genetics, University of Barcelona, Barcelona E-08028, Spain.
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Garcia-Fernàndez
1] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona E-08028, Spain [2] Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, CSIC, IDIBAPS, Barcelona E-08036, Spain.
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Trullas
1] Department of Cell Biology, University of Barcelona, Barcelona E-08028, Spain [2] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona E-08028, Spain [3] Fundación CIEN, Vallecas E-28031, Madrid, Spain [4] Vall d'Hebron Institut de Recerca, Barcelona E-08035, Spain.
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Soriano
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D051186:Armadillo Domain Proteins / Q000737:chemistry / Q000235:genetics*; D001369:Axons / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D019610:Cytoprotection / Q000187:drug effects*; D056426:Genetic Loci; D016678:Genome / Q000235:genetics*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D063154:Mitochondrial Dynamics / Q000235:genetics*; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D026801:Synteny / Q000235:genetics
D016229:Amyloid beta-Peptides; D051186:Armadillo Domain Proteins; D020033:Protein Isoforms; D016547:Kinesins