Mitochondrial damage drives T-cell immunometabolic paralysis after major surgery

Hirschberger, Simon; Müller, Martin B; Mascolo, Hannah; Seitz, Melissa; Nibler, Stefan; Effinger, David; Lu, Kun; Büch, Joscha; Bender, Martin; Kammerer, Tobias; Peterß, Sven; Kleigrewe, Karin; Abele, Miriam; Barth, Teresa; Kushnir, Olga; Imhof, Axel; Dietzel, Steffen; Wegener, Bernd; Sowa, Ralf; Vogel, Frank; Lamm, Peter; Tomasi, Roland; Unger, Kristian; Sperandio, Markus; Kilger, Erich; Kreth, Simone; Hübner, Max (2025): Mitochondrial damage drives T-cell immunometabolic paralysis after major surgery. EMBO Molecular Medicine, 17 (12). pp. 3329-3354. ISSN 1757-4684

Abstract

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.

• Doc-Type: Article (LMU Hospital)
• Organisational unit (Faculties): 07 Medicine; 07 Medicine > Medical Center of the University of Munich > Clinic for Anaesthesiology; 07 Medicine > Medical Center of the University of Munich > Cardiac Surgery Clinic and Polyclinic
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 447514737
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892