Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology.
Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology.
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DOI：
10.1038/s41590-021-01048-3
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发表时间：
2021-11
影响因子：
30.5
通讯作者：
Reddy, Pavan
中科院分区：
文献类型：
--
作者：
Fujiwara, Hideaki;Seike, Keisuke;Brooks, Michael D.;Mathew, Anna, V;Kovalenko, Ilya;Pal, Anupama;Lee, Ho-Joon;Peltier, Daniel;Kim, Stephanie;Liu, Chen;Oravecz-Wilson, Katherine;Li, Lu;Sun, Yaping;Byun, Jaeman;Maeda, Yoshinobu;Wicha, Max S.;Saunders, Tom;Rehemtulla, Alnawaz;Lyssiotis, Costas A.;Pennarthur, Subramanian;Reddy, Pavan
T细胞对肠上皮细胞（IEC）的损伤导致移植物抗宿主病（GVHD）、炎症性肠病（IBD）和免疫检查点阻断（ICB）介导的结肠炎。但是对于影响疾病严重程度的靶细胞内在特征知之甚少。在此，我们从几种不同的T细胞介导的结肠炎体内模型中鉴定了IEC中氧化磷酸化的破坏和琥珀酸水平的增加。代谢通量的研究，补充成像和蛋白质分析确定IEC固有的琥珀酸脱氢酶A（SDHA），线粒体复合物II的一个组成部分，在导致这些代谢的改变中断。IEC内在SDHA在介导疾病严重程度中的相关性通过补充化学和遗传实验方法得到证实，并在人类临床样本中得到验证。这些数据确定了IEC特异性线粒体复合物II组分SDHA的改变在调节T细胞介导的肠道疾病的严重程度中的关键作用。
Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune checkpoint blockade (ICB) mediated colitis. But little is known about the target cell intrinsic features that influence disease severity. Herein we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses identified disruption of IEC intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC specific mitochondrial complex II component SDHA in the regulation of the severity of T cell mediated intestinal diseases.
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影响因子：
32.4
作者：
Campbell EL;Bruyninckx WJ;Kelly CJ;Glover LE;McNamee EN;Bowers BE;Bayless AJ;Scully M;Saeedi BJ;Golden-Mason L;Ehrentraut SF;Curtis VF;Burgess A;Garvey JF;Sorensen A;Nemenoff R;Jedlicka P;Taylor CT;Kominsky DJ;Colgan SP
通讯作者：
Colgan SP
影响因子：
30.5
作者：
Mathewson ND;Jenq R;Mathew AV;Koenigsknecht M;Hanash A;Toubai T;Oravecz-Wilson K;Wu SR;Sun Y;Rossi C;Fujiwara H;Byun J;Shono Y;Lindemans C;Calafiore M;Schmidt TM;Honda K;Young VB;Pennathur S;van den Brink M;Reddy P
通讯作者：
Reddy P
影响因子：
29
作者：
Donohoe DR;Garge N;Zhang X;Sun W;O'Connell TM;Bunger MK;Bultman SJ
通讯作者：
Bultman SJ
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
64.5
作者：
Dotiwala F;Sen Santara S;Binker-Cosen AA;Li B;Chandrasekaran S;Lieberman J
通讯作者：
Lieberman J