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

• 成果类型: Article
• 署名作者: Yang, Xu; Lia, Guilin; Loud, Pengbo; Zhang, Mingxin; Yao, Kai; Xiao, Jintao; Chen, Yiqian; Xu, Jiuzhi; Tian, Shengyuan; Deng, Min; Pan, Yuwei; Li, Mengzhen; Wu, Xi; Liu, Ruiqi; Shi, Xiaojing; Tian, Yuhua; Yu, Lu; Ke, Hao; Jiao, Baowei; Cong, Yingzi; Plikus, Maksim V.; Liu, Xiaowei; Yu, Zhengquan; Lv, Cong
• 署名单位: Zhengzhou University; China Agricultural University; Ankang University; Central South University; Chinese Academy of Sciences; Kunming Institute of Zoology, CAS; Northwestern University; Feinberg School of Medicine; University of California System; University of California Irvine; China Agricultural University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10301
• DOI: 10.1073/pnas.2307395120
• 发表日期: 2024-01-02
• 关键词: nad(+) depletion; bowel-disease; dna-damage; tdp-43; mutations; contributes; colitis; neurons; barrier; nmn

摘要

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 alpha-ketoglutarate dioxygenase in mitochondria, rescued TDP-43 deficiency- induced cell death and intestinal inflammation. Furthermore, TDP-43 protein levels were significantly inversely correlated with gamma-H2A.X and p-MLKL levels in clinical IBD samples, suggesting the clinical relevance of TDP-43 deficiency- induced mitochondrion- dependent necroptosis. Taken together, these findings identify a unique pathogenic mechanism that links oxidative stress to intestinal inflammation and provide a potent and valid strategy for IBD intervention.