C5 Inhibitor Nomacopan Preserves Mitochondrial Integrity and Function in Combined Traumatic Brain Injury and Hemorrhagic Shock 2259501

Abstract Introduction Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) induce robust complement activation and systemic inflammation that impair mitochondrial homeostasis. Mitochondrial dysfunction contributes to multi-organ failure following trauma. Nomacopan, a dual inhibitor of complement component C5 and leukotriene B4 (LTB4), has shown anti-inflammatory effects, but its impact on trauma-induced mitochondrial injury remains unclear. Methods In Sprague—Dawley rats subjected to TBI + HS, mitochondrial ultrastructure and oxidative phosphorylation (OXPHOS) were assessed in different tissues using transmission electron microscopy and high-resolution respirometry to characterize trauma-induced mitochondrial injury. To evaluate therapeutic potential, a porcine TBI + HS model was treated with Nomacopan, and mitochondrial morphology, bioenergetic function, and structural proteins were analyzed by electron microscopy and Western blot. Results In rats, TBI + HS caused severe mitochondrial swelling, disrupted cristae, and a significant decrease in OXPHOS capacity across cortex and myocardium. Respiratory chain complex activities were markedly reduced, indicating impaired bioenergetic function. In pigs, Nomacopan treatment markedly improved mitochondrial ultrastructure, including restoration of cristae integrity and reduction of swelling. Functional analysis revealed significant recovery of OXPHOS and respiratory chain activity compared with untreated TBI + HS controls. Furthermore, Nomacopan preserved mitochondrial structural proteins, including Mitofilin and OPA1, suggesting stabilization of the inner membrane architecture. Conclusion These findings demonstrate that TBI + HS induces profound mitochondrial injury in rodents and that complement C5 inhibition with Nomacopan effectively restores mitochondrial structure and function in a translational large animal model. Complement blockade represents a promising therapeutic strategy for mitigating systemic mitochondrial dysfunction following severe trauma. Funding Source DOW Topic Categories Immune Mechanisms of Human Disease (HUM)