Institute for Ophthalmic Research, Department for Ophthalmology, Tübingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Sci Rep. 2020 Jun 25;10(1):10320. doi: 10.1038/s41598-020-67292-z.
Polymorphisms in the Complement Factor H (CFH) gene, coding for the Factor H protein (FH), can increase the risk for age-related macular degeneration (AMD). AMD-associated CFH risk variants, Y402H in particular, impair FH function leading to complement overactivation. Whether this alone suffices to trigger AMD pathogenesis remains unclear. In AMD, retinal homeostasis is compromised due to the dysfunction of retinal pigment epithelium (RPE) cells. To investigate the impact of endogenous FH loss on RPE cell balance, we silenced CFH in human hTERT-RPE1 cells. FH reduction led to accumulation of C3, at both RNA and protein level and increased RPE vulnerability toward oxidative stress. Mild hydrogen-peroxide exposure in combination with CFH knock-down led to a reduction of glycolysis and mitochondrial respiration, paralleled by an increase in lipid peroxidation, which is a key aspect of AMD pathogenesis. In parallel, cell viability was decreased. The perturbations of energy metabolism were accompanied by transcriptional deregulation of several glucose metabolism genes as well as genes modulating mitochondrial stability. Our data suggest that endogenously produced FH contributes to transcriptional and metabolic homeostasis and protects RPE cells from oxidative stress, highlighting a novel role of FH in AMD pathogenesis.
补体因子 H (CFH) 基因的多态性可导致因子 H 蛋白 (FH) 编码发生改变，从而增加年龄相关性黄斑变性 (AMD) 的发病风险。与 AMD 相关的 CFH 风险变异，尤其是 Y402H，可损害 FH 的功能，导致补体过度激活。但这是否足以引发 AMD 的发病机制尚不清楚。在 AMD 中，由于视网膜色素上皮 (RPE) 细胞功能障碍，视网膜内稳态受到损害。为了研究内源性 FH 缺失对 RPE 细胞平衡的影响，我们在人 hTERT-RPE1 细胞中沉默了 CFH。FH 减少导致 C3 在 RNA 和蛋白质水平上的积累，并增加了 RPE 对氧化应激的易感性。温和的过氧化氢暴露与 CFH 敲低相结合，导致糖酵解和线粒体呼吸减少，同时脂质过氧化增加，这是 AMD 发病机制的一个关键方面。与此同时，细胞活力降低。能量代谢的紊乱伴随着几个葡萄糖代谢基因以及调节线粒体稳定性的基因的转录失调。我们的数据表明，内源性产生的 FH 有助于转录和代谢稳态，并保护 RPE 细胞免受氧化应激，这突出了 FH 在 AMD 发病机制中的新作用。
