title: Mitochondrial Protection by Exogenous Otx2 in Mouse Retinal Neurons.
abstract: OTX2 (orthodenticle homeobox 2) haplodeficiency causes diverse defects in mammalian visual systems ranging from retinal dysfunction to anophthalmia. We find that the retinal dystrophy of Otx2(+/GFP) heterozygous knockin mice is mainly due to the loss of bipolar cells and consequent deficits in retinal activity. Among bipolar cell types, OFF-cone bipolar subsets, which lack autonomous Otx2 gene expression but receive Otx2 proteins from photoreceptors, degenerate most rapidly in Otx2(+/GFP) mouse retinas, suggesting a neuroprotective effect of the imported Otx2 protein. In support of this hypothesis, retinal dystrophy in Otx2(+/GFP) mice is prevented by intraocular injection of Otx2 protein, which localizes to the mitochondria of bipolar cells and facilitates ATP synthesis as a part of mitochondrial ATP synthase complex. Taken together, our findings demonstrate a mitochondrial function for Otx2 and suggest a potential therapeutic application of OTX2 protein delivery in human retinal dystrophy.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, South Korea.
authors.forename: Hyoung-Tai
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.
authors.forename: Soung Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, South Korea.
authors.forename: Young-In
authors.initials: YI
authors.lastname: Sohn
authors.affiliation: Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: Sun-Sook
authors.initials: SS
authors.lastname: Paik
authors.affiliation: INSERM, U968, Paris 75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France; CNRS, UMR_7210, Paris 75012, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Caplette
authors.affiliation: INSERM, U968, Paris 75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France; CNRS, UMR_7210, Paris 75012, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Simonutti
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, South Korea.
authors.forename: Kyeong Hwan
authors.initials: KH
authors.lastname: Moon
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, South Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, South Korea.
authors.forename: Kwang Wook
authors.initials: KW
authors.lastname: Min
authors.affiliation: Nano-Bio Electron Microscopy Research Group, Korea Basic Science Institute (KBSI), Daejeon 305-806, South Korea.
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Biological Disaster Analysis Group, Korea Basic Science Institute (KBSI), Daejeon 305-806, Korea.
authors.forename: Dong-Gi
authors.initials: DG
authors.lastname: Lee
authors.affiliation: Institute of Genetics and Biophysics, Adriano Buzzati-Traverso, Via Pietro Castellino 111, 80131 Napoli, Italy; IRCCS Neuromed, Pozzilli, IS 86077, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Simeone
authors.affiliation: Institut de Biologie Valrose, University of Nice Sophia Antipolis, UMR UNS/CNRS 7277/INSERM 1091, Nice 06108, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lamonerie
authors.affiliation: Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Biological Disaster Analysis Group, Korea Basic Science Institute (KBSI), Daejeon 305-806, Korea.
authors.forename: Jong-Soon
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Nano-Bio Electron Microscopy Research Group, Korea Basic Science Institute (KBSI), Daejeon 305-806, South Korea.
authors.forename: Hee-Seok
authors.initials: HS
authors.lastname: Kweon
authors.affiliation: INSERM, U968, Paris 75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France; CNRS, UMR_7210, Paris 75012, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Picaud
authors.affiliation: Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea.
authors.forename: In-Beom
authors.initials: IB
authors.lastname: Kim
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 301-721, South Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, South Korea. Electronic address: jinwookim@kaist.ac.kr.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D058449:Intravitreal Injections; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051857:Otx Transcription Factors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051245:Retinal Bipolar Cells / Q000187:drug effects* / Q000378:metabolism; D058499:Retinal Dystrophies / Q000188:drug therapy*
chemical_list: D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D000255:Adenosine Triphosphate