Hippocampal Bioenergetics and Metabolic Profiling Identifies Fatty Acid Oxidation as a Potential Therapeutic Target in Traumatic Brain Injury
Abstract
Traumatic brain injury (TBI) causes lasting neurological impairments, particularly learning and memory deficits associated with hippocampal damage. Emerging evidence suggests that hippocampal vulnerability may be linked to bioenergetic dysfunction, though its role remains poorly defined. A deeper understanding of post-TBI metabolic disturbances and their association with pathological outcomes could reveal novel therapeutic targets. In this study, we conducted functional bioenergetic assessments and multi-omics analyses on hippocampal slices using a mouse controlled cortical impact model of TBI. Seahorse analysis revealed a significant reduction in mitochondrial oxidative phosphorylation in dentate gyrus (DG) slices at day 1 (acute phase), which recovered by day 7 (subacute phase) post-TBI. Metabolomic profiling revealed acute impairments in purine nucleotide, glucose, amino acid, and fatty acid metabolism, most of which normalized by day 7. Isotope tracing indicated enhanced octanoate-derived fatty acid oxidation (FAO) in DG slices at day 7 post-TBI. Proteomics confirmed suppressed purine metabolism at day 1 across hippocampal subregions, while FAO remained preserved at day 1 and became significantly elevated by day 7, suggesting a compensatory metabolic adaptation. Administration of sodium octanoate, a medium-chain fatty acid, at 1 h post-TBI enhanced mitochondrial respiration at 24 h, reduced microglial counts at 48 h, and attenuated neurodegeneration by day 3. These…
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