Abstract
Traumatic brain injury (TBI) results in mitochondrial dysfunction and induction of lipid peroxidation (LP). Lipid peroxidation-derived neurotoxic aldehydes such as 4-HNE and acrolein bind to mitochondrial proteins, inducing additional oxidative damage and further exacerbating mitochondrial dysfunction and LP. Mitochondria are heterogeneous, consisting of both synaptic and non-synaptic populations. Synaptic mitochondria are reported to be more vulnerable to injury; however, this is the first study to characterize the temporal profile of synaptic and non-synaptic mitochondria following TBI, including investigation of respiratory dysfunction and oxidative damage to mitochondrial proteins between 3 and 120 h following injury. These results indicate that synaptic mitochondria are indeed the more vulnerable population, showing both more rapid and severe impairments than non-synaptic mitochondria. By 24 h, synaptic respiration is significantly impaired compared to synaptic sham, whereas non-synaptic respiration does not decline significantly until 48 h. Decreases in respiration are associated with increases in oxidative damage to synaptic and non-synaptic mitochondrial proteins at 48 h and 72 h, respectively. These results indicate that the therapeutic window for mitochondria-targeted pharmacological neuroprotectants to prevent respiratory dysfunction is shorter for the more vulnerable synaptic mitochondria than for the non-synaptic population.
Original language | English |
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Pages (from-to) | 265-283 |
Number of pages | 19 |
Journal | Neuroscience |
Volume | 386 |
DOIs | |
State | Published - Aug 21 2018 |
Bibliographical note
Funding Information:This work was supported by 5R01 NS083405 , 5R01 NS084857 , 5P30 NS0512220 , F30 NS096876 , and funding from the Kentucky Spinal Cord & Head Injury Research Trust (KSCHIRT). Rachel Hill was responsible for optimizing the isolation protocol for the non-synaptic and synaptic mitochondria from cortical tissue, performed all the experiments, and carried out most of the data analysis and overall organization and presentation of the data as well as statistical analysis, wrote most of the manuscript, designed graphs/figures and performed statistical analyses. Jacqueline Kulbe contributed to writing of the manuscript and some analysis of respiration and western blot data. Indrapal Singh assisted in mitochondrial respiratory assays and Juan Wang (Amy) assisted with animal work. Edward Hall supervised the experiments in his lab and contributed to the writing and organization of the manuscript.
Publisher Copyright:
© 2018 IBRO
Keywords
- lipid peroxidation
- non-synaptic mitochondria
- oxidative damage
- synaptic mitochondria
- traumatic brain injury
ASJC Scopus subject areas
- Neuroscience (all)