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Release Date:11/14/2023 12:57:00 AM

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.

 

Congratulations to Prof. Peng Zhang from Tongji University (China), Prof. Xing Liu from Chinese Academy of Sciences (China), and Prof. Judy Lieberman from Harvard Medical School, for their wonderful work published in Immunity (IF=43.47)!

 

 

InvivoChem is proud to provide Professors Zhang, Liu and Lieberman with our high-quality product VBIT-4 (Cat #: V2258; CAS #: 2086257-77-2, VDAC1 inhibitor)for this research.

 

 

 

 

References: Immunity. 2023 Nov 14;56(11):2523-2541.e8. doi: 10.1016/j.immuni.2023.10.004.

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