Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA, USA.
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
Sci Rep. 2018 Oct 11;8(1):15175. doi: 10.1038/s41598-018-33290-5.
Mitochondrial-derived peptides (MDPs) are rapidly emerging therapeutic targets to combat development of neurodegenerative diseases. SHLP2 (small humanin-like peptide 2) is a newly discovered MDP that is coded from the MT-RNR2 (Mitochondrially encoded 16S rRNA) gene in mitochondrial DNA (mtDNA). In the current study, we examined the biological consequences of treatment with exogenously-added SHLP2 in an in vitro human transmitochondrial age-related macular degeneration (AMD) ARPE-19 cell model. In AMD cells, we observed significant down-regulation of the MDP-coding MT-RNR2 gene, and remarkably reduced levels of all five oxidative phosphorylation (OXPHOS) complex I-V protein subunits that are involved in the electron transport chain; these results suggested mitochondrial toxicity and abnormal OXPHOS complex protein subunits' levels in AMD cells. However, treatment of AMD cells with SHLP2: (1) restored the normal levels of OXPHOS complex protein subunits, (2) prevented loss of viable cells and mitochondria, (3) increased the number of mtDNA copies, (4) induced anti-apoptotic effects, and (5) attenuated amyloid-β-induced cellular and mitochondrial toxicity. Cumulatively, our findings established the protective role of SHLP2 in AMD cells in vitro. In conclusion, this novel study supports the merit of SHLP2 in the treatment of AMD, a primary retinal disease that is a leading cause of blindness among the elderly population in the United States as well as worldwide.
线粒体衍生肽 (MDPs) 是治疗神经退行性疾病的新兴治疗靶点。SHLP2（小分子人类素样肽 2）是一种新发现的 MDP，它是由线粒体 DNA（mtDNA）中的 MT-RNR2（线粒体编码 16S rRNA）基因编码的。在本研究中，我们在体外人类传递粒体相关性年龄相关性黄斑变性 (AMD) ARPE-19 细胞模型中研究了外源性添加 SHLP2 的生物学后果。在 AMD 细胞中，我们观察到 MDP 编码的 MT-RNR2 基因显著下调，并且参与电子传递链的所有五个氧化磷酸化 (OXPHOS) 复合物 I-V 蛋白亚基的水平显著降低；这些结果表明 AMD 细胞中线粒体毒性和异常 OXPHOS 复合物蛋白亚基水平。然而，用 SHLP2 处理 AMD 细胞：(1) 恢复了 OXPHOS 复合物蛋白亚基的正常水平，(2) 防止了存活细胞和线粒体的丧失，(3) 增加了 mtDNA 拷贝数，(4) 诱导了抗凋亡作用，以及 (5) 减轻了淀粉样蛋白-β诱导的细胞和线粒体毒性。总之，我们的发现确立了 SHLP2 在体外 AMD 细胞中的保护作用。总之，这项新研究支持 SHLP2 在治疗 AMD 中的价值，AMD 是美国以及全球老年人群中导致失明的主要视网膜疾病。
