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

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, Hao Ke, Baowei Jiao, Yingzi CongMaksim V. Plikus, Xiaowei Liu*, Zhengquan Yu*, Cong Lv*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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 protein levels were significantly inversely correlated with γ-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.

Original languageEnglish (US)
Article numbere2307395120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number1
DOIs
StatePublished - 2024

Funding

ACKNOWLEDGMENTS. We thank the members of the laboratory animal center in China Agricultural University for their assistance in animal care. This study was supported by grants from the National Basic Research Program of China (2022YFA1104001,2022YFC3602102,2022YFD1300403,and 2021YFF1000603), the National Natural Science Foundation of China 82025006, 82230017 (to Z.Y.), 82300635 (to X.Y.), 82000498, 82270588 (to C.L.), 88220019 (to X.L.), and the Postdoctoral Science Foundation of China 2022M723412 (to X.Y.).

Keywords

  • TDP-43 | R-loop
  • inflammatory bowel disease
  • | necroptosis |

ASJC Scopus subject areas

  • General

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