Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury

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. The response of mitochondria in the pediatric brain to injury has limited investigation, despite evidence that developing brain’s response differs from the adult, especially in diffuse non-impact TBI. We perform 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 was increased in both hippocampal and cortical tissue, with decreased respiratory ratios of convergent oxidative phosphorylation through complex I and II, compared to sham animals, indicating uncoupling of oxidative phosphorylation at 24 hours. 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. In addition, mitochondrial respiration 24 hours after diffuse TBI that varies by location within the brain. Finally, we conclude 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.

Using Serum Amino Acids to Predict Traumatic Brain Injury: A Systematic Approach to Utilize Multiple Biomarkers

“…These brain biomechanical loads initiate a cascade of short-and long-term cellular and sub-cellular biochemical and metabolomic alterations in the brain which cause primary injury and secondary injury that evolves over time [1] and can lead to long-term neurodegeneration [2]. These biochemical and metabolomic alterations first appear in the brain tissue and then, by crossing a number of barriers, manifest in biofluids such as cerebrospinal fluid (CSF), blood, saliva and urine [1][2][3][4][5][6][7][8][9][10][11][12]. Therefore, biofluids contain valuable information about the occurrence and progression of TBI and thus recently have been explored as a source for potential biomarkers to diagnose TBI, as well as to assess its severity, monitor its progression, predict patient outcomes, and determine the effectiveness of therapeutic interventions [1,4,5,[9][10][11][13][14][15][16][17][18][19].…”

Rutin Acid Ameliorates Neural Apoptosis Induced by Traumatic Brain Injury via Mitochondrial Pathways in Mice

“…Secondary brain injury after trauma may result from oxidative stress, metabolic dysfunction, excitotoxicity, inflammatory response or vascular abnormalities [2,15,16]. Oxidative stress is caused by the generation of ROS in response to TBI [17,18,19].…”

“…High levels of ROS resulting from excitotoxicity and the failure of endogenous antioxidant mechanisms induce lipid peroxidation, protein nitration and DNA damage [20,21]. However, mitochondria play an important role in the exacerbation of the injured brain by activating signaling pathways via ROS production or by inducing mitochondria-dependent apoptosis [2,22]. There are many studies indicating that mitochondrial biogenesis is limited after TBI.…”

“…The injured brain responds by activating endogenous reparative processes to counter neurodegeneration or remodel the brain toward the enhancement of functional recovery. Reactive oxygen species (ROS) are produced primarily in mitochondria, the impairment of which increases ROS production, damaging mitochondrial proteins, DNA and lipids, disrupting cellular Ca 2+ homeostasis, inducing apoptosis and causing metabolic failure [1,2]. Apoptotic mechanisms must be tightly regulated to prevent neuronal death after TBI, the regulation of which includes control of the mitochondrial apoptotic pathway.…”

Epigenetic changes following traumatic brain injury and their implications for outcome, recovery and therapy

“…Specifically, changes in mitochondrial integrity, movement and bioenergetics can alter the course of repair [7, 32, 52, 53, 60, 63, 73, 81]. Mitochondria are considered the powerhouse organelle of the cell, where they play a critical role in cerebral metabolism through the process of oxidative phosphorylation, which drives the production of ATP.…”