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Wei-Hua Lee, Hitoshi Higuchi, Erica Macke, Che Liu, Li-Fang Chu, John B Troy, Robert F Mullins, Joseph Takahashi, Lawrence Pinto, Akihiro Ikeda; The role of Tmem135 in retinal aging and mitochondrial dynamics. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5422.
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© ARVO (1962-2015); The Authors (2016-present)
Our long-term goal is to understand the molecular mechanism causing retinal diseases associated with aging. We screened for, and identified an ENU-induced mutant mouse strain showing accelerated retinal aging phenotypes. In this study, we aimed to positionally clone the gene responsible for these early aging phenotypes, and identify the molecular function of the gene product.
Phenotypic characterization of FUN025 mice was performed by histological analyses. Genetic mapping and high-throughput sequencing techniques were used to identify the genetic mutation in FUN025 mice. Localization of TMEM135 was determined by immunofluorescence, immunoelectron microscopy, and western blot in mouse, monkey and human cells as well as in the mouse retina. The role of TMEM135 in mitochondrial dynamics was studied in mouse fibroblasts (MFs) from wild-type, FUN025 and Tmem135 transgenic mice. Mitochondrial functions in MFs were measured using XF24 seahorse analyzer and flow cytometer.
We observed lipofuscin accumulation, enhanced inflammation, and photoreceptor degeneration in the FUN025 retina, which are common symptoms in age-related macular degeneration. By positional cloning, we identified a mutation in the gene encoding transmembrane protein 135 (Tmem135), previously known as a longevity gene in C. elegans. Our studies using the cell culture system revealed that TMEM135 proteins form punctate structures on mitochondria within the cell. Analysis of the mitochondria from FUN025 MFs and MFs that overexpress wild-type Tmem135 indicated that TMEM135 is involved in mitochondrial fission. Mitochondrial functions were impaired in cultured FUN025 mutant cells. The level of oxidative stress and the sensitivity to oxidative stress were increased in cultured FUN025 mutant cells and mutant retina.
Our study demonstrates that Tmem135 is a novel gene involved in aging mechanisms. Our findings suggest that the regulation of mitochondrial dynamics through TMEM135 is critical for protecting cells from environmental stress and controlling the progression of the aging process. Unbalanced mitochondrial dynamics may lead to impaired mitochondrial functions, and thus increase the risk of developing age-related retinal diseases.
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