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Mitochondrial dysfunction in PTSD: A mechanism to understand trauma susceptibility? - Psychopharmacology Rationale and Objectives Post-Traumatic Stress Disorder (PTSD) is a complex mental health condition that arises following exposure to traumatic events. Converging evidence suggests mitochondrial dysfunction and brain energy metabolism impairment in its pathophysiology. Thus, examining mitochondrial data from both preclinical and experimental medicine studies may help us to have a deeper understanding of the pathophysiological mechanisms underlying PTSD. Methods Using PubMed, Scopus and Web of Science online databases, we conducted a search for peer-reviewed manuscripts targeting both mitochondrial-related activity and PTSD. Our search yielded 43 studies in total, including 29 in rodent models and 15 clinical studies. Results Preclinical studies reported a decrease in energy metabolism with a reduction in adenosine triphosphate (ATP) level, upregulation of genes associated with ATP synthesis, impairment of the glycolytic pathway, citric acid cycle and oxidative phosphorylation pathways and increased oxidative stress and neuronal apoptosis in the brain, or systemically. In the clinical setting, studies identified 1108 participants with PTSD and 312 with partial PTSD, with these individuals showing alterations in energy production, mitochondrial DNA copy number (mtDNAcn) and elevated oxidative stress. Risperidone and AC-5216—a selective ligand for TSPO—emerged as potential treatments. Conclusion Our synthesis of the published findings indicates a notable overlap between results from both animal models and humans which could show a potential usage of mitochondrial-related targets as biomarkers or for drug discovery. Additionally, these results highlight the need for future research in describing whether mitochondrial dysfunction is a cause or a symptom of PTSD. https://link.springer.com/article/10.1007/s00213-025-06900-0?utm_source=rct_congratemailt&utm_medium=email&utm_campaign=oa_20251010&utm_content=10.1007%2Fs00213-025-06900-0