| A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3. | |
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MedLine Citation:
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PMID: 20627962 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Costeff Syndrome, which is caused by mutations in the OPTIC ATROPHY 3 (OPA3) gene, is an early-onset syndrome characterized by urinary excretion of 3-methylglutaconic acid (MGC), optic atrophy and movement disorders, including ataxia and extrapyramidal dysfunction. The OPA3 protein is enriched in the inner mitochondrial membrane and has mitochondrial targeting signals, but a requirement for mitochondrial localization has not been demonstrated. We find zebrafish opa3 mRNA to be expressed in the optic nerve and retinal layers, the counterparts of which in humans have high mitochondrial activity. Transcripts of zebrafish opa3 are also expressed in the embryonic brain, inner ear, heart, liver, intestine and swim bladder. We isolated a zebrafish opa3 null allele for which homozygous mutants display increased MGC levels, optic nerve deficits, ataxia and an extrapyramidal movement disorder. This correspondence of metabolic, ophthalmologic and movement abnormalities between humans and zebrafish demonstrates a phylogenetic conservation of OPA3 function. We also find that delivery of exogenous Opa3 can reduce increased MGC levels in opa3 mutants, and this reduction requires the mitochondrial localization signals of Opa3. By manipulating MGC precursor availability, we infer that elevated MGC in opa3 mutants derives from extra-mitochondrial HMG-CoA through a non-canonical pathway. The opa3 mutants have normal mitochondrial oxidative phosphorylation profiles, but are nonetheless sensitive to inhibitors of the electron transport chain, which supports clinical recommendations that individuals with Costeff Syndrome avoid mitochondria-damaging agents. In summary, this paper introduces a faithful Costeff Syndrome model and demonstrates a requirement for mitochondrial OPA3 to limit HMG-CoA-derived MGC and protect the electron transport chain against inhibitory compounds. |
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Authors:
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Wuhong Pei; Lisa E Kratz; Isa Bernardini; Raman Sood; Tohei Yokogawa; Heidi Dorward; Carla Ciccone; Richard I Kelley; Yair Anikster; Harold A Burgess; Marjan Huizing; Benjamin Feldman |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural |
Journal Detail:
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Title: Development (Cambridge, England) Volume: 137 ISSN: 1477-9129 ISO Abbreviation: Development Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-07-14 Completed Date: 2010-08-24 Revised Date: 2011-08-03 |
Medline Journal Info:
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Nlm Unique ID: 8701744 Medline TA: Development Country: England |
Other Details:
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Languages: eng Pagination: 2587-96 Citation Subset: IM |
Affiliation:
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Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acyl Coenzyme A
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metabolism Alleles Amino Acid Metabolism, Inborn Errors / genetics Animals Disease Models, Animal Electron Transport Glutarates / metabolism* Membrane Proteins / genetics, metabolism* Mitochondria / genetics, metabolism* Models, Biological Models, Genetic Optic Atrophy / genetics Phosphorylation Proteins / genetics* Zebrafish Zebrafish Proteins / genetics*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Acyl Coenzyme A; 0/Glutarates; 0/Membrane Proteins; 0/OPA3 protein, human; 0/OPA3 protein, zebrafish; 0/Proteins; 0/Zebrafish Proteins; 1553-55-5/3-hydroxy-3-methylglutaryl-coenzyme A; 5746-90-7/3-methylglutaconic acid |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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