title: A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3.
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.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
authors.forename: Wuhong
authors.initials: W
authors.lastname: Pei
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Kratz
authors.forename: Isa
authors.initials: I
authors.lastname: Bernardini
authors.forename: Raman
authors.initials: R
authors.lastname: Sood
authors.forename: Tohei
authors.initials: T
authors.lastname: Yokogawa
authors.forename: Heidi
authors.initials: H
authors.lastname: Dorward
authors.forename: Carla
authors.initials: C
authors.lastname: Ciccone
authors.forename: Richard I
authors.initials: RI
authors.lastname: Kelley
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: Harold A
authors.initials: HA
authors.lastname: Burgess
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Benjamin
authors.initials: B
authors.lastname: Feldman
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004579:Electron Transport; D005977:Glutarates / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008957:Models, Genetic; D009896:Optic Atrophy / Q000235:genetics; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000214:Acyl Coenzyme A; D005977:Glutarates; D008565:Membrane Proteins; C443108:OPA3 protein, human; C551582:OPA3 protein, zebrafish; D011506:Proteins; D029961:Zebrafish Proteins; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; C022034:3-methylglutaconic acid