Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells
Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells
复制标题
DOI：
10.1038/s41598-020-67292-z
复制
发表时间：
2020-06-25
影响因子：
4.6
通讯作者：
Ueffing, Marius
中科院分区：
文献类型：
--
作者：
Armento, Angela;Honisch, Sabina;Ueffing, Marius
编码因子H蛋白（FH）的补体因子H（CFH）基因多态性可增加年龄相关性黄斑变性（AMD）的风险。AMD相关的CFH风险变体，特别是Y402H，损害FH功能，导致补体过度激活。这是否足以引发AMD发病机制尚不清楚。在AMD中，由于视网膜色素上皮（RPE）细胞的功能障碍，视网膜稳态受损。为了研究内源性FH损失对RPE细胞平衡的影响，我们沉默了人hTERT-RPE 1细胞中的CFH。FH减少导致C3在RNA和蛋白质水平的积累，并增加RPE对氧化应激的脆弱性。轻度过氧化氢暴露结合CFH敲低导致糖酵解和线粒体呼吸减少，随后脂质过氧化增加，这是AMD发病机制的一个关键方面。同时，细胞活力降低。能量代谢的扰动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，突出了FH在AMD发病机制中的新作用。
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.