美国波士顿儿童医院Judy Lieberman等研究人员合作发现，Gasdermin D对线粒体内膜和外膜的渗透作用可加速和加强焦亡。2023年11月3日，相关论文在线发表在《免疫》杂志上。

研究人员发现N端的成孔Gasdermin D（GSDMD）片段（GSDMD-NT）会迅速损伤线粒体内膜和外膜（OMM），导致线粒体数量减少、线粒体自噬、ROS、跨膜电位丧失、氧化磷酸化（OXPHOS）减弱以及线粒体蛋白和DNA从基质和膜间隙中释放出来。在质膜损伤之前，一旦GSDMD被切割，线粒体损伤就会发生。线粒体损伤与B细胞淋巴瘤2家族无关，取决于GSDMD-NT与心磷脂的结合。

通过基因敲减心磷脂合成酶（Crls1）或将心磷脂转移到OMM的扰乱酶（Plscr3），可抑制线粒体损伤的典型和非经典炎症小体激活、焦亡和炎症细胞因子释放。肿瘤中磷脂翻转酶-3（PLSCR3）的缺乏会损害焦亡诱导的抗肿瘤免疫。因此，线粒体损伤在焦亡中起着至关重要的作用。

据悉，GSDMD激活的炎症细胞死亡（焦亡）会导致线粒体损伤，但其基本机制和功能后果在很大程度上还不清楚。

附：英文原文

Title: Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis

Author: Rui Miao, Cong Jiang, Winston Y. Chang, Haiwei Zhang, Jinsu An, Felicia Ho, Pengcheng Chen, Han Zhang, Caroline Junqueira, Dulguun Amgalan, Felix G. Liang, Junbing Zhang, Charles L. Evavold, Iva Hafner-Bratkovi, Zhibin Zhang, Pietro Fontana, Shiyu Xia, Markus Waldeck-Weiermair, Youdong Pan, Thomas Michel, Liron Bar-Peled, Hao Wu, Jonathan C. Kagan, Richard N. Kitsis, Peng Zhang, Xing Liu, Judy Lieberman

Issue&Volume:

Abstract: Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrialdamage, but its underlying mechanism and functional consequences are largely unknown.Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damagedboth inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrialnumbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation(OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembranespace. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasmamembrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 familyand depended on GSDMD-NT binding to cardiolipin. Canonical and noncanonical inflammasomeactivation of mitochondrial damage, pyroptosis, and inflammatory cytokine releasewere suppressed by genetic ablation of cardiolipin synthase (Crls1) or the scramblase (Plscr3) that transfers cardiolipin to the OMM. Phospholipid scramblase-3 (PLSCR3) deficiencyin a tumor compromised pyroptosis-triggered anti-tumor immunity. Thus, mitochondrialdamage plays a critical role in pyroptosis.

DOI: 10.1016/j.immuni.2023.10.004

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00444-2