CEP89 is required for mitochondrial metabolism and neuronal function in man and fly
| Autor: | Lillian Eshuis, Erika Viragh, Annette Schenck, Licio Collavin, Zoltan Asztalos, Bregje W.M. van Bon, Richard J. Rodenburg, Jan A.M. Smeitink, Bert B.A. de Vries, Leo G.J. Nijtmans, Patrik Verstreken, Melissa Vos, Martijn A. Huynen, Nicole de Leeuw, Mariken Ruiter, Merel A.W. Oortveld, Falko Hofmann, Michaela Fenckova, Judith A. Besseling, Lenke Asztalos, Bonnie Nijhof, Anna Castells-Nobau, Jamie M. Kramer |
|---|---|
| Přispěvatelé: | B. W. M., van Bon, M. A. W., Oortveld, L. G., Nijtman, M., Fenckova, B., Nijhof, J., Besseling, M., Vo, J. M., Kramer, N., de Leeuw, A., Castells Nobau, L., Asztalo, E., Viragh, M., Ruiter, F., Hofmann, L., Eshui, Collavin, Licio, M. A., Huynen, Z., Asztalo, P., Verstreken, R. J., Rodenburg, J. A., Smeitink, B. B. A., de Vrie, A., Schenck |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Mitochondrial intermembrane space
genetics/metabolism Cytochrome-c Oxidase Deficiency Gene Expression Cell Cycle Proteins Mitochondrion p53 interacting protein Cytosol 0302 clinical medicine Drosophila Proteins genetics/metabolism Drosophila melanogaster Child Genetics (clinical) Neurons 0303 health sciences Gene knockdown Homozygote Mitochondrial medicine Energy and redox metabolism [IGMD 8] General Medicine Mitochondria Cell biology Protein Transport Mitochondrial medicine [IGMD 8] Drosophila melanogaster mitochondrial fusion Organ Specificity Gene Knockdown Techniques Energy and redox metabolism Mitochondrial medicine [NCMLS 4] Drosophila Female Microtubule-Associated Proteins Biology Polymorphism Single Nucleotide Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3] Genomic disorders and inherited multi-system disorders [IGMD 3] 03 medical and health sciences Genetics Animals Humans Learning Cytochrome c oxidase Molecular Biology Loss function 030304 developmental biology Pathogenesis and modulation of inflammation Infection and autoimmunity [N4i 1] Molecular biology Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory [NCMLS 6] Disease Models Animal Mutation Synapses biology.protein DNAJA3 Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6] Chromosomes Human Pair 19 Gene Deletion 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics, 22, 15, pp. 3138-3151 Human Molecular Genetics Human Molecular Genetics; Vol 22 Human Molecular Genetics, 22, 3138-3151 |
| ISSN: | 0964-6906 |
| Popis: | It is estimated that the human mitochondrial proteome consists of 1000-1500 distinct proteins. The majority of these support the various biochemical pathways that are active in these organelles. Individuals with an oxidative phosphorylation disorder of unknown cause provide a unique opportunity to identify novel genes implicated in mitochondrial biology. We identified a homozygous deletion of CEP89 in a patient with isolated complex IV deficiency, intellectual disability and multisystemic problems. CEP89 is a ubiquitously expressed and highly conserved gene of unknown function. Immunocytochemistry and cellular fractionation experiments showed that CEP89 is present both in the cytosol and in the mitochondrial intermembrane space. Furthermore, we ascertained in vitro that downregulation of CEP89 resulted in a severe decrease in complex IV in-gel activity and altered mobility, suggesting that the complex is aberrantly formed. Two-dimensional BN-SDS gel analysis revealed that CEP89 associates with a high-molecular weight complex. Together, these data confirm a role for CEP89 in mitochondrial metabolism. In addition, we modeled CEP89 loss of function in Drosophila. Ubiquitous knockdown of fly Cep89 decreased complex IV activity and resulted in complete lethality. Furthermore, Cep89 is required for mitochondrial integrity, membrane depolarization and synaptic transmission of photoreceptor neurons, and for (sub)synaptic organization of the larval neuromuscular junction. Finally, we tested neuronal Cep89 knockdown flies in the light-off jump reflex habituation assay, which revealed its role in learning. We conclude that CEP89 proteins play an important role in mitochondrial metabolism, especially complex IV activity, and are required for neuronal and cognitive function across evolution. ispartof: Human Molecular Genetics vol:22 issue:15 pages:3138-3151 ispartof: location:England status: published |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|