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

	Excessive nucleic acid R- loops induce mitochondria- dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation
	Yang, X; Lia, G; Loud, P; Zhang, MX; Yao, K; Xiao, JT; Chen, YQ; Xu, JZ; Tian, SY; Deng, M; Pan, YW; Li, MZ; Wu, X; Liu, RQ; Shi, XJ; Tian, YH; Yu, L; Ke, H; Jiao, BW; Cong, YZ; Plikus, MV; Liu, XW; Yu, ZQ; Lv, C
	2024
发表期刊	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN	0027-8424
卷号	121 期号:1
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.
收录类别	sci
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/14261
专题	科研部门_发育的印迹调控与进化学（焦保卫）
推荐引用方式 GB/T 7714	Yang, X,Lia, G,Loud, P,et al. Excessive nucleic acid R- loops induce mitochondria- dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2024,121(1).
APA	Yang, X.,Lia, G.,Loud, P.,Zhang, MX.,Yao, K.,...&Lv, C.(2024).Excessive nucleic acid R- loops induce mitochondria- dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,121(1).
MLA	Yang, X,et al."Excessive nucleic acid R- loops induce mitochondria- dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 121.1(2024).

条目包含的文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
2024073139.pdf（6731KB）	期刊论文	出版稿	开放获取	CC BY-NC-SA	请求全文