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Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury
Todd J Kilbaugh1, Michael Karlsson2, Ann-Christine Duhaime3
1Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Blvd., Philadelphia, PA 19104, USA.
Insights
Pediatric traumatic brain injury (TBI) disrupts mitochondrial function, altering energy production in the brain. This study reveals key changes in oxidative phosphorylation, offering new therapeutic targets for injured children.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Pediatric Traumatology
Background:
- Traumatic brain injury (TBI) is a major cause of childhood mortality globally.
- Mitochondrial dysfunction significantly contributes to secondary injury cascades following TBI.
- The pediatric brain's response to TBI, particularly diffuse injuries, remains under-investigated and may differ from adult responses.
Purpose of the Study:
- To investigate mitochondrial bioenergetics in the pediatric brain following diffuse TBI.
- To evaluate alterations in mitochondrial respiration and oxidative phosphorylation in response to rapid non-impact rotational (RNR) injury.
- To identify potential therapeutic targets by understanding location-specific mitochondrial changes.
Main Methods:
- Utilized a swine model to simulate diffuse TBI (RNR injury).
- Employed high-resolution respirometry with a substrate-uncoupler-inhibitor-titration protocol to assess mitochondrial function in cortical and hippocampal tissues.
- Measured respiration relative to citrate synthase activity to control for mitochondrial content variations.
Main Results:
- Diffuse RNR injury increased complex II-driven respiration in the hippocampus relative to mitochondrial content.
- LEAK (State 4o) respiration elevated in both cortex and hippocampus, with reduced respiratory ratios indicating oxidative phosphorylation uncoupling at 24 hours post-injury.
- Complex I contribution to respiration decreased, while complex II contribution increased in the hippocampus.
Conclusions:
- Mitochondrial respiration following diffuse TBI in pediatric brains is regionally specific.
- Significant uncoupling of oxidative phosphorylation and altered convergent respiration pathways were observed.
- These findings highlight potential therapeutic strategies targeting mitochondrial dysfunction in pediatric TBI.
Abstract:
Traumatic brain injury (TBI) is an important health problem, and a leading cause of death in children worldwide. Mitochondrial dysfunction is a critical component of the secondary TBI cascades. Mitochondrial response in the pediatric brain has limited investigation, despite evidence that the developing brain's response differs from that of the adult, especially in diffuse non-impact TBI. We performed a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a swine model of diffuse TBI (rapid non-impact rotational injury: RNR), and examined the cortex and hippocampus. A substrate-uncoupler-inhibitor-titration protocol examined the role of the individual complexes as well as the uncoupled maximal respiration. Respiration per mg of tissue was also related to citrate synthase activity (CS) as an attempt to control for variability in mitochondrial content following injury. Diffuse RNR stimulated increased complex II-driven respiration relative to mitochondrial content in the hippocampus compared to shams. LEAK (State 4o) respiration increased in both regions, with decreased respiratory ratios of convergent oxidative phosphorylation through complex I and II, compared to sham animals, indicating uncoupling of oxidative phosphorylation at 24h. The study suggests that proportionately, complex I contribution to convergent mitochondrial respiration was reduced in the hippocampus after RNR, with a simultaneous increase in complex-II driven respiration. Mitochondrial respiration 24h after diffuse TBI varies by location within the brain. We concluded that significant uncoupling of oxidative phosphorylation and alterations in convergent respiration through complex I- and complex II-driven respiration reveals therapeutic opportunities for the injured at-risk pediatric brain.
