title: MouseTmem135mutation reveals a mechanism involving mitochondrial dynamics that leads to age-dependent retinal pathologies.
abstract: While the aging process is central to the pathogenesis of age-dependent diseases, it is poorly understood at the molecular level. We identified a mouse mutant with accelerated aging in the retina as well as pathologies observed in age-dependent retinal diseases, suggesting that the responsible gene regulates retinal aging, and its impairment results in age-dependent disease. We determined that a mutation in the transmembrane 135 (Tmem135) is responsible for these phenotypes. We observed localization of TMEM135 on mitochondria, and imbalance of mitochondrial fission and fusion in mutantTmem135as well asTmem135overexpressing cells, indicating that TMEM135 is involved in the regulation of mitochondrial dynamics. Additionally, mutant retina showed higher sensitivity to oxidative stress. These results suggest that the regulation of mitochondrial dynamics through TMEM135 is critical for protection from environmental stress and controlling the progression of retinal aging. Our study identified TMEM135 as a critical link between aging and age-dependent diseases.
authors.affiliation: Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States.
authors.forename: Wei-Hua
authors.identifier: 0000-0002-8032-0279
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Higuchi
authors.affiliation: Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States.|McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, United States.
authors.forename: Sakae
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Macke
authors.affiliation: Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takimoto
authors.affiliation: McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, United States.|Department of Pediatrics, University of Wisconsin-Madison, Madison, United States.
authors.forename: Bikash R
authors.initials: BR
authors.lastname: Pattnaik
authors.affiliation: Institute for Molecular Virology, University of Wisconsin-Madison, Madison, United States.|McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States.
authors.forename: Che
authors.initials: C
authors.lastname: Liu
authors.affiliation: Morgridge Institute for Research, Madison, United States.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Chu
authors.affiliation: Department of Neurobiology, Northwestern University, Evanston, United States.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Siepka
authors.affiliation: Transgenic Mouse Facility, Biotechnology Center, University of Wisconsin-Madison, Madison, United States.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Krentz
authors.affiliation: Translational Genomics Facility, Biotechnology Center, University of Wisconsin-Madison, Madison, United States.
authors.forename: C Dustin
authors.initials: CD
authors.lastname: Rubinstein
authors.affiliation: Institute for Molecular Virology, University of Wisconsin-Madison, Madison, United States.|McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kalejta
authors.affiliation: Morgridge Institute for Research, Madison, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Thomson
authors.affiliation: Department of Ophthalmology and Visual, University of Iowa, Iowa City, United States.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Mullins
authors.affiliation: Department of Neuroscience, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Joseph S
authors.identifier: 0000-0003-0384-8878
authors.initials: JS
authors.lastname: Takahashi
authors.affiliation: Department of Neurobiology, Northwestern University, Evanston, United States.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Pinto
authors.affiliation: Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States.|McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, United States.
authors.forename: Akihiro
authors.identifier: 0000-0001-8440-3891
authors.initials: A
authors.lastname: Ikeda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics*; D000375:Aging; D000818:Animals; D051379:Mice; D008928:Mitochondria / Q000737:chemistry; D063154:Mitochondrial Dynamics; D050505:Mutant Proteins / Q000032:analysis / Q000235:genetics*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D012164:Retinal Diseases / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C545285:Fam220a protein, mouse; D050505:Mutant Proteins; D009687:Nuclear Proteins
keywords: ENU; age-dependent retinal diseases; aging; cell biology; mitochondrial dynamics; mouse; neuroscience; retina; retinal pigment epithelium