Mitochondrial damage drives T-cell immunometabolic paralysis after major surgery
Cytotoxic T cell (CTL) dysfunction is a hallmark of immune paralysis after major surgery, increasing susceptibility to severe nosocomial infections and contributing to mortality in critically ill patients. The mechanisms remain poorly understood. We demonstrate that reactive oxygen species (ROS) released by myeloid-derived suppressor cells (MDSC) transiently emerging after surgery, drive perioperative CTL immunoparalysis. These ROS damage CTL mitochondria, triggering secondary mitochondrial ROS amplification and overwhelming antioxidant defenses. The resulting oxidative cascade impairs oxidative phosphorylation and suppresses CTL effector function. Concurrently, stress-induced mitochondrial hyperfusion disrupts fission-dependent translocation to the immunological synapse, exacerbating bioenergetic failure. MitoTEMPO, a mitochondria-targeted antioxidant, partially mitigates these effects, highlighting mitochondrial stabilization as a potential strategy to prevent perioperative immune dysfunction.
Authors
- Hannah Mascolo
- Roland Tomasi (ORCID: https://orcid.org/0000-0001-8484-0047)
- Miriam Abele (ORCID: https://orcid.org/0000-0003-0084-2999)
- David Effinger (ORCID: https://orcid.org/0000-0002-1720-1365)
- Martin Bender (ORCID: https://orcid.org/0000-0002-9590-4728)
- Steffen Dietzel (ORCID: https://orcid.org/0000-0001-5725-3242)
- Teresa K. Barth
- Simon Hirschberger (ORCID: https://orcid.org/0000-0002-4221-7377)
- Simone Kreth (ORCID: https://orcid.org/0000-0002-0073-2098)
- Kristian Unger (ORCID: https://orcid.org/0000-0002-0374-2320)
- Peter Lamm
- Tobias Kammerer (ORCID: https://orcid.org/0000-0001-8920-7187)
- Olga Kushnir
- Melissa Seitz (ORCID: https://orcid.org/0009-0006-3176-1496)
- Bernd Wegener (ORCID: https://orcid.org/0000-0001-6304-1377)
- Frank Vogel
- Markus Sperandio (ORCID: https://orcid.org/0000-0002-7689-3613)
- Sven Peterß (ORCID: https://orcid.org/0000-0003-1880-152X)
- Max Hübner (ORCID: https://orcid.org/0009-0002-3940-1138)
- Erich Kilger
- Axel Imhof (ORCID: https://orcid.org/0000-0003-2993-8249)
- Karin Kleigrewe (ORCID: https://orcid.org/0000-0002-7718-0252)
- Martin B. Müller
- Ralf Sowa (ORCID: https://orcid.org/0009-0002-3283-2875)
- Kun Lü (ORCID: https://orcid.org/0009-0007-8660-5826)
- J Buch
- Stefan Nibler
Institutions
- Center for Integrated Protein Science Munich (DE)
- LMU Klinikum (DE)
- Nephrologisches Zentrum Goettingen (DE)
- München Klinik (DE)
- German Centre for Cardiovascular Research (DE)
- Centre of Experimental Medicine of the Slovak Academy of Sciences (SK)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-11-03
- DOI
- https://doi.org/10.1038/s44321-025-00324-1
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.80