Excessive nucleic acid R-loops induce mitochondria-dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation

作者：Xu Yang, Guilin Li, Pengbo Lou, Mingxin Zhang, Kai Yao, Jintao Xiao, Yiqian Chen, Jiuzhi Xu, Shengyuan Tian, Min Deng, Yuwei Pan, Mengzhen Li, Xi Wu, Ruiqi Liu, Xiaojing Shi, Yuhua Tian, Lu Yu, Ke Hao, Baowei Jiao, Yingzi Cong, Maksim V. Plikus, Xiaowei Liu, Zhengquan Yu, Cong Lv · 发表于：Proceedings of the National Academy of Sciences · 年份：2023 · DOI：10.1073/pnas.2307395120 · 被引用次数：44 · 研究领域：Trace Elements in Health、RNA regulation and disease、RNA Research and Splicing

Oxidative stress, which can be activated by a variety of environmental risk factors, has been implicated as an important pathogenic factor for inflammatory bowel disease (IBD). However, how oxidative stress drives IBD onset remains elusive. Here, we found that oxidative stress was strongly activated in inflamed tissues from both ulcerative colitis patients and Crohn’s disease patients, and it caused nuclear-to-cytosolic TDP-43 transport and a reduction in the TDP-43 protein level. To investigate the function of TDP-43 in IBD, we inducibly deleted exons 2 to 3 of Tardbp (encoding Tdp-43) in mouse intestinal epithelium, which disrupted its nuclear localization and RNA-processing function. The deletion gave rise to spontaneous intestinal inflammation by inducing epithelial cell necroptosis. Suppression of the necroptotic pathway with deletion of Mlkl or the RIP1 inhibitor Nec-1 rescued colitis phenotypes. Mechanistically, disruption of nuclear TDP-43 caused excessive R-loop accumulation, which triggered DNA damage and genome instability and thereby induced PARP1 hyperactivation, leading to subsequent NAD + depletion and ATP loss, consequently activating mitochondrion-dependent necroptosis in intestinal epithelial cells. Importantly, restoration of cellular NAD + levels with NAD + or NMN supplementation, as well as suppression of ALKBH7, an α-ketoglutarate dioxygenase in mitochondria, rescued TDP-43 deficiency-induced cell death and intestinal inflammation. Furthermore, TDP-43 pr...