Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis
Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis
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DOI：
10.1016/j.immuni.2023.10.004
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发表时间：
2023-11-14
期刊：
影响因子：
32.4
通讯作者：
Lieberman, Judy
中科院分区：
文献类型：
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作者：
Miao, Rui;Jiang, Cong;Lieberman, Judy
Gasdermin D （GSDMD）激活的炎症细胞死亡（pyroptosis）可引起线粒体损伤，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端形成孔的GSDMD片段（GSDMD- nt）迅速破坏线粒体内外膜（OMMs），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，线粒体蛋白和DNA从基质和膜间空间释放。线粒体损伤发生在质膜损伤之前。线粒体损伤独立于b细胞淋巴瘤2家族，依赖于GSDMD-NT与心磷脂的结合。通过基因消融心磷脂合成酶（Crls1）或将心磷脂转移到OMM的超燃酶（Plscr3），可抑制线粒体损伤、焦亡和炎性细胞因子释放的典型和非典型炎性体活化。肿瘤中磷脂重组酶-3 （PLSCR3）缺乏损害了焦热触发的抗肿瘤免疫。因此，线粒体损伤在焦亡中起关键作用。
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 mem-branes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane poten-tial, 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.