Lee Wei-Hua, Higuchi Hitoshi, Ikeda Sakae, Macke Erica L, Takimoto Tetsuya, Pattnaik Bikash R, Liu Che, Chu Li-Fang, Siepka Sandra M, Krentz Kathleen J, Rubinstein C Dustin, Kalejta Robert F, Thomson James A, Mullins Robert F, Takahashi Joseph S, Pinto Lawrence H, Ikeda Akihiro
Department of Medical Genetics, University of Wisconsin-Madison, Madison, United States.
McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, United States.
Elife. 2016 Nov 15;5:e19264. doi: 10.7554/eLife.19264.
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 () is responsible for these phenotypes. We observed localization of TMEM135 on mitochondria, and imbalance of mitochondrial fission and fusion in mutant as well as 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.
虽然衰老过程是年龄依赖性疾病发病机制的核心，但在分子水平上人们对此了解甚少。我们鉴定出一种小鼠突变体，其视网膜衰老加速，且出现了年龄依赖性视网膜疾病中观察到的病理特征，这表明相关基因调节视网膜衰老，其功能受损会导致年龄依赖性疾病。我们确定跨膜蛋白135（TMEM135）中的一个突变是造成这些表型的原因。我们观察到TMEM135定位于线粒体，并且在突变体以及过表达细胞中线粒体分裂和融合失衡，表明TMEM135参与线粒体动力学的调节。此外，突变体视网膜对氧化应激表现出更高的敏感性。这些结果表明，通过TMEM135调节线粒体动力学对于抵御环境应激和控制视网膜衰老进程至关重要。我们的研究确定TMEM135是衰老与年龄依赖性疾病之间的关键联系。
Zotero 插件
