Cerebellar mitochondrial dysfunction and concomitant multi-system fatty acid oxidation defects are sufficient to discriminate PTSD-like and resilient male mice.

The impact of trauma on mental health is complex with poorly understood underlying mechanisms. Mitochondrial dysfunction is increasingly implicated in psychopathologies and mood disorders, including post-traumatic stress disorder (PTSD). We hypothesized that defects in mitochondrial energy metabolism in the cerebellum, an emerging region of interest in the pathobiology of mood disorders, would be associated with PTSD-like symptomatology, and that PTSD-like symptomatology would correlate with the activities of the mitochondrial electron transport chain (mtETC) and fatty acid oxidation (FAO) pathways. We assayed mitochondrial energy metabolism and fatty acid profiling using targeted metabolomics in mice exposed to a recently developed paradigm for PTSD-induction. 48 wild type male FVB.129P2 mice were exposed to a trauma, and PTSD-like and resilient animals were identified using behavioral profiling. Mice displaying PTSD-like symptomatology displayed reduced mtETC complex activities in the cerebellum, and cerebellar mtETC complex activity negatively correlated with PTSD-like symptomatology. PTSD-like animals also displayed fatty acid profiles consistent with FAO dysfunction in both cerebellum and plasma. Machine learning analysis of all biochemical measures in this cohort of animals also identified plasma acetylcarnitine, along with reduced activity of cerebellar complex I and IV as well as succinate:cytochrome c oxidoreductase as state predictive discriminators of PTSD-symptomatology. Our data also suggest that trauma-induced impaired mtETC function in the cerebellum and concomitant impaired multi-system fatty acid oxidation are candidate drivers of PTSD-like behavior in mice. These bioenergetic and metabolic changes may offer an informative window into the underlying biology and highlight novel potential targets for diagnostics and therapeutic interventions in PTSD.

The role of suboptimal mitochondrial function in vulnerability to post-traumatic stress disorder.

Post-traumatic stress disorder remains the most significant psychiatric condition associated with exposure to a traumatic event, though rates of traumatic event exposure far outstrip incidence of PTSD. Mitochondrial dysfunction and suboptimal mitochondrial function have been increasingly implicated in several psychopathologies, and recent genetic studies have similarly suggested a pathogenic role of mitochondria in PTSD. Mitochondria play a central role in several physiologic processes underlying PTSD symptomatology, including abnormal fear learning, brain network activation, synaptic plasticity, steroidogenesis, and inflammation. Here we outline several potential mechanisms by which inherited (genetic) or acquired (environmental) mitochondrial dysfunction or suboptimal mitochondrial function, may contribute to PTSD symptomatology and increase susceptibility to PTSD. The proposed pathogenic role of mitochondria in the pathophysiology of PTSD has important implications for prevention and therapy, as antidepressants commonly prescribed for patients with PTSD have been shown to inhibit mitochondrial function, while alternative therapies shown to improve mitochondrial function may prove more efficacious.