Gasdermin D 对线粒体内膜和外膜的透化可加速并增强细胞焦亡。
Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.
发表日期：2023 Oct 31
作者：
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-Bratkovič, 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
来源：
CYTOKINE & GROWTH FACTOR REVIEWS
摘要：
Gasdermin D (GSDMD) 激活的炎症细胞死亡（焦亡）会导致线粒体损伤，但其潜在机制和功能后果在很大程度上尚不清楚。在这里，我们发现 N 端成孔 GSDMD 片段 (GSDMD-NT) 快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、跨膜电位损失、氧化磷酸化减弱 (OXPHOS) ），并从基质和膜间隙释放线粒体蛋白和 DNA。 GSDMD 在质膜损伤之前被裂解，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，并且依赖于 GSDMD-NT 与心磷脂的结合。线粒体损伤、焦亡和炎性细胞因子释放的典型和非典型炎症小体激活通过心磷脂合酶 (Crls1) 或将心磷脂转移至 OMM 的扰动酶 (Plscr3) 的基因消融而受到抑制。肿瘤中的磷脂加扰酶 3 (PLSCR3) 缺乏会损害细胞焦亡引发的抗肿瘤免疫。因此，线粒体损伤在细胞焦亡中起着关键作用。版权所有 © 2023 Elsevier Inc. 保留所有权利。
Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 family and depended on GSDMD-NT binding to cardiolipin. Canonical and noncanonical inflammasome activation of mitochondrial damage, pyroptosis, and inflammatory cytokine release were suppressed by genetic ablation of cardiolipin synthase (Crls1) or the scramblase (Plscr3) that transfers cardiolipin to the OMM. Phospholipid scramblase-3 (PLSCR3) deficiency in a tumor compromised pyroptosis-triggered anti-tumor immunity. Thus, mitochondrial damage plays a critical role in pyroptosis.Copyright © 2023 Elsevier Inc. All rights reserved.