Abstract
Metabolic uncoupling has been well-characterized during the first minutes-to-days after a traumatic brain injury (TBI), yet mitochondrial bioenergetics during the weeks-to-months after a brain injury is poorly defined, particularly after a mild TBI. We hypothesized that a closed head injury (CHI) would be associated with deficits in mitochondrial bioenergetics at one month after the injury. A significant decrease in state-III (adenosine triphosphate production) and state-V (complex-I) driven mitochondrial respiration was found at one month post-injury in adult C57Bl/6J mice. Isolation of synaptic mitochondria demonstrated that the deficit in state-III and state-V was primarily neuronal. Injured mice had a temporally consistent deficit in memory recall at one month post-injury. Using proton magnetic resonance spectroscopy (1H MRS) at 7-Tesla, we found significant decreases in phosphocreatine, N-Acetylaspartic acid, and total choline. We also found regional variations in cerebral blood flow, including both hypo- and hyperperfusion, as measured by a pseudocontinuous arterial spin labeling MR sequence. Our results highlight a chronic deficit in mitochondrial bioenergetics associated with a CHI that may lead toward a novel approach for neurorestoration after a mild TBI. MRS provides a potential biomarker for assessing the efficacy of candidate treatments targeted at improving mitochondrial bioenergetics.
Highlights
Mitochondria are essential for neuronal health and synaptic function
Using a mouse model of mild traumatic brain injury (TBI), induced by a closed head injury (CHI), we found strong support for our hypothesis that a mild TBI would result in a premature aging of synaptic mitochondria
Experiments used four-month-old C57BL/6J mice and included an equal ratio of male and female for all end points. This project used a total of 204 mice: 36 mice were used for mitochondrial isolation; 19 mice were used for behavioral assays; 37 mice were used for pseudocontinuous arterial spin labeling (pCASL) and 1H-MRS experiment 1; 112 mice were used for 1H-MRS experiment 2; 22 of the 204 mice were not included in the data analysis for reasons described in the following method sections for each end point
Summary
Mitochondria are essential for neuronal health and synaptic function. Mitochondrial dysfunction is well-described during the minutes-to-days after a traumatic brain injury (TBI), but there is a critical knowledge gap concerning mitochondrial bioenergetic deficits beyond the acute period after a brain injury. The commonalities of mitochondrial dysfunction after TBI and in neurodegenerative diseases suggest a potential mechanism whereby TBI induces a premature aging of mitochondria— synaptic mitochondria. Using a mouse model of mild TBI, induced by a closed head injury (CHI), we found strong support for our hypothesis that a mild TBI would result in a premature aging of synaptic mitochondria. We found a decrease in mitochondrial bioenergetics at one month post-injury, in neuronal synaptic mitochondrial bioenergetics, which corresponded temporally with deficits in spatial memory as measured in the radial arm water maze
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