Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States
Hitoshi Higuchi
Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States
Sakae Ikeda
Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, United States
Erica L Macke
Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States
Tetsuya Takimoto
Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States
Bikash R Pattnaik
McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, United States; Department of Pediatrics, University of Wisconsin-Madison, Madison, United States
Che Liu
Institute for Molecular Virology, University of Wisconsin-Madison, Madison, United States; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States
Li-Fang Chu
Morgridge Institute for Research, Madison, United States
Sandra M Siepka
Department of Neurobiology, Northwestern University, Evanston, United States
Kathleen J Krentz
Transgenic Mouse Facility, Biotechnology Center, University of Wisconsin-Madison, Madison, United States
C Dustin Rubinstein
Translational Genomics Facility, Biotechnology Center, University of Wisconsin-Madison, Madison, United States
Robert F Kalejta
Institute for Molecular Virology, University of Wisconsin-Madison, Madison, United States; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, United States
James A Thomson
Morgridge Institute for Research, Madison, United States
Robert F Mullins
Department of Ophthalmology and Visual, University of Iowa, Iowa City, United States
Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, United States
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 mutant Tmem135 as well as Tmem135 overexpressing 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.
