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PMID:20627962

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Citation

Pei, W, Kratz, LE, Bernardini, I, Sood, R, Yokogawa, T, Dorward, H, Ciccone, C, Kelley, RI, Anikster, Y, Burgess, HA, Huizing, M and Feldman, B (2010) A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3. Development 137:2587-96

Abstract

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.

Links

PubMed PMC2927703 Online version:10.1242/dev.043745

Keywords

Acyl Coenzyme A/metabolism; Alleles; Amino Acid Metabolism, Inborn Errors/genetics; Animals; Disease Models, Animal; Electron Transport; Glutarates/metabolism; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mitochondria/genetics; Mitochondria/metabolism; Models, Biological; Models, Genetic; Optic Atrophy/genetics; Phosphorylation; Proteins/genetics; Zebrafish; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:OPA3

involved_in

GO:0007626: locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-101007-4

P

Seeded From UniProt

complete

DANRE:OPA3

involved_in

GO:0031413: regulation of buoyancy

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-101007-4

P

Seeded From UniProt

complete

DANRE:OPA3

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DANRE:OPA3

involved_in

GO:0050881: musculoskeletal movement

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-101007-4

P

Seeded From UniProt

complete


See also

References

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