• W Brad Hubbard, Binoy Joseph, Malinda Spry, Hemendra J Vekaria, Kathryn E Saatman, and Patrick G Sullivan.
• 1 Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky.
• J. Neurotrauma. 2019 Apr 15; 36 (8): 1252-1263.

AbstractMild traumatic brain injuries (mTBI), accounting for more than 80% of TBIs, can cause cognitive and behavioral impairments, the severity and duration of which increase after additional mTBIs. While mTBI does not cause widespread neuronal death, the mechanisms underlying increased cellular susceptibility to subsequent head impacts remain unknown. To investigate the hypothesis that altered mitochondrial bioenergetics underlie cellular vulnerability to repeated insults, we employed a mouse model of mild closed head injury (CHI) to examine mitochondrial function and oxidative stress, because these mechanisms are often intertwined. Mitochondrial respiration was assayed (Seahorse XFe24 Flux Analyzer) from cortex and hippocampus collected at 6 h, 24 h, 48 h, and 96 h post-injury. State III (adenosine diphosphate [ADP]-mediated) respiration was significantly decreased in the hippocampal mitochondria of the CHI group compared with sham at 48 h post-injury. Further, cortex-derived mitochondria exhibited a decrease in State III respiration at 24 h and 48 h post-injury. No significant differences were observed at 6 h or 96 h post-injury in either region of interest. A second CHI repeated either 48 h or 96 h after the first did not worsen State III respiration at 48 h after the final injury compared with a single CHI, but CHI repeated at a 48 h interval prolonged cortical mitochondrial dysfunction to 96 h after the final injury. Markers of oxidative stress were significantly elevated after two CHIs delivered 48 h apart, but not after single CHI or two CHI delivered 96 h apart. This study establishes that mTBI results in early mitochondrial dysfunction, which may be a determinant for cellular vulnerability to repeated head impacts. Thus, therapies targeting mitochondrial impairment could improve outcomes after repeated mTBI.

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