2. Academic Validation
  3. 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

  • Immunity. 2023 Oct 31:S1074-7613(23)00444-2. doi: 10.1016/j.immuni.2023.10.004.
Rui Miao 1,  Cong Jiang 2,  Winston Y Chang 3,  Haiwei Zhang 3,  Jinsu An 3,  Felicia Ho 3,  Pengcheng Chen 4,  Han Zhang 2,  Caroline Junqueira 5,  Dulguun Amgalan 6,  Felix G Liang 6,  Junbing Zhang 7,  Charles L Evavold 8,  Iva Hafner-Bratkovič 9,  Zhibin Zhang 10,  Pietro Fontana 11,  Shiyu Xia 11,  Markus Waldeck-Weiermair 12,  Youdong Pan 13,  Thomas Michel 12,  Liron Bar-Peled 7,  Hao Wu 11,  Jonathan C Kagan 14,  Richard N Kitsis 6,  Peng Zhang 15,  Xing Liu 16,  Judy Lieberman 17
Affiliations

Affiliations

  • 1 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
  • 2 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; Key Laboratory of RNA Science and Engineering, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China.
  • 3 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Key Laboratory of RNA Science and Engineering, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China.
  • 5 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG 30190-009, Brazil.
  • 6 Departments of Medicine and Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
  • 7 Center for Cancer Research, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
  • 8 Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA 02139, USA.
  • 9 Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Synthetic Biology and Immunology, National Institute of Chemistry and EN-FIST Centre of Excellence and Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.
  • 10 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 11 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 12 Brigham and Women's Hospital, Department of Medicine, Cardiovascular Division, Harvard Medical School, Boston, MA 02115, USA.
  • 13 Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 14 Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 15 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China. Electronic address: [email protected].
  • 16 Key Laboratory of RNA Science and Engineering, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: [email protected].
  • 17 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 37924812 DOI: 10.1016/j.immuni.2023.10.004
Abstract

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.

Keywords

CRLS1; GSDMD; IL-1; PLSCR3; cardiolipin; mitochondria; pyroptosis.

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