2. Academic Validation
  3. Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis

Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis

  • Cell. 2025 Dec 11;188(25):7155-7174.e25. doi: 10.1016/j.cell.2025.11.002.
Yaqiu Wang 1,  Jianlin Lu 1,  Alexandre F Carisey 2,  Sangappa B Chadchan 1,  Ha Won Lee 3,  R K Subbarao Malireddi 1,  Bhesh Raj Sharma 1,  Nagakannan Pandian 1,  Rebecca E Tweedell 1,  Gustavo Palacios 1,  Nathalie Becerra Mora 4,  Camenzind G Robinson 4,  Aaron Pitre 4,  Peter Vogel 5,  Taosheng Chen 3,  Michael P Murphy 6,  Thirumala-Devi Kanneganti 7
Affiliations

Affiliations

  • 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 2 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 3 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 4 Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 5 Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 6 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
  • 7 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: thirumala-devi.kanneganti@stjude.org.
PMID: 41317732 DOI: 10.1016/j.cell.2025.11.002
Abstract

The combination of innate immune activation and metabolic disruption plays critical roles in many diseases, often leading to mitochondrial dysfunction and oxidative stress that drive pathogenesis. However, mechanistic regulation under these conditions remains poorly defined. Here, we report a distinct lytic cell death mechanism induced by innate immune signaling and metabolic disruption, independent of Caspase activity and previously described Pyroptosis, PANoptosis, Necroptosis, Ferroptosis, and oxeiptosis. Instead, mitochondria undergoing Bax/BAK1/BID-dependent oxidative stress maintained prolonged plasma membrane contact, leading to local oxidative damage, a process we termed mitoxyperiosis. This process then caused membrane lysis and cell death, termed mitoxyperilysis. mTORC2 regulated the cell death, and mTOR inhibition restored cytoskeletal activity for lamellipodia to retract and mobilize mitochondria away from the membrane, preserving integrity. Activating this pathway in vivo regressed tumors in an mTORC2-dependent manner. Overall, our results identify a lytic cell death modality in response to the synergism of innate immune signaling and metabolic disruption.

Keywords

carbon starvation; cytokine; inflammasome; inflammatory cell death; innate immunity; mTOR; metabolism; mitochondria; oxidative damage; tumor.

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