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Structural and functional damage sustained by mitochondria after traumatic brain injury in the rat: Evidence for differentially sensitive populations in the cortex and hippocampus

Lifshitz, J; Friberg, Hans LU ; Neumar, RW; Raghupathi, R; Welsh, FA; Janmey, P; Saatman, KE; Wieloch, Tadeusz LU ; Grady, MS and McIntosh, TK (2003) In Journal of Cerebral Blood Flow and Metabolism 23(2). p.219-231
Abstract
The cellular and molecular pathways initiated by traumatic brain injury (TBI) may compromise the function and structural integrity of mitochondria, thereby contributing to cerebral metabolic dysfunction and cell death. The extent to which TBI affects regional mitochondrial populations with respect to structure, function, and swelling was assessed 3 hours and 24 hours after lateral fluid-percussion brain injury in the rat. Significantly less mitochondrial protein was isolated from the injured compared with uninjured parietotemporal cortex, whereas comparable yields were obtained from the hippocampus. After injury, cortical and hippocampal tissue ATP concentrations declined significantly to 60% and 40% of control, respectively, in the... (More)
The cellular and molecular pathways initiated by traumatic brain injury (TBI) may compromise the function and structural integrity of mitochondria, thereby contributing to cerebral metabolic dysfunction and cell death. The extent to which TBI affects regional mitochondrial populations with respect to structure, function, and swelling was assessed 3 hours and 24 hours after lateral fluid-percussion brain injury in the rat. Significantly less mitochondrial protein was isolated from the injured compared with uninjured parietotemporal cortex, whereas comparable yields were obtained from the hippocampus. After injury, cortical and hippocampal tissue ATP concentrations declined significantly to 60% and 40% of control, respectively, in the absence of respiratory deficits in isolated mitochondria. Mitochondria with ultrastructural morphologic damage comprised a significantly greater percent of the population isolated from injured than uninjured brain. As determined by photon correlation spectroscopy, the mean mitochondrial radius decreased significantly in injured cortical populations (361 +/- 40 nm at 24 hours) and increased significantly in injured hippocampal populations (442 +/- 36 at 3 hours) compared with uninjured populations (Ctx: 418 +/- 44; Hipp: 393 +/- 24). Calcium-induced deenergized swelling rates of isolated mitochondrial populations were significantly slower in injured compared with uninjured samples, suggesting that injury alters the kinetics of mitochondrial permeability transition (MPT) pore activation. Cyclosporin A (CsA)-insensitive swelling was reduced in the cortex, and CsA-sensitive and CsA-insensitive swelling both were reduced in the hippocampus, demonstrating that regulated MPT pores remain in mitochondria isolated from injured brain. A proposed mitochondrial population model synthesizes these data and suggests that cortical mitochondria may be depleted after TBI, with a physically smaller, MPT-regulated population remaining. Hippocampal mitochondria may sustain damage associated with ballooned membranes and reduced MPT pore calcium sensitivity. The heterogeneous mitochondrial response to TBI may underlie posttraumatic metabolic dysfunction and contribute to the pathophysiology of TBI. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
scatter, dynamic light, cell death, photon correlation spectroscopy, swelling, mitochondrial, head injury, mitochondrial permeability transition
in
Journal of Cerebral Blood Flow and Metabolism
volume
23
issue
2
pages
219 - 231
publisher
Nature Publishing Group
external identifiers
  • wos:000180893800009
  • pmid:12571453
  • scopus:0346788718
ISSN
1559-7016
DOI
10.1097/00004647-200302000-00009
language
English
LU publication?
yes
id
ede039a3-00fa-4f60-9ad4-1e60943d4fe4 (old id 318618)
date added to LUP
2007-09-16 12:44:55
date last changed
2018-01-07 08:39:39
@article{ede039a3-00fa-4f60-9ad4-1e60943d4fe4,
  abstract     = {The cellular and molecular pathways initiated by traumatic brain injury (TBI) may compromise the function and structural integrity of mitochondria, thereby contributing to cerebral metabolic dysfunction and cell death. The extent to which TBI affects regional mitochondrial populations with respect to structure, function, and swelling was assessed 3 hours and 24 hours after lateral fluid-percussion brain injury in the rat. Significantly less mitochondrial protein was isolated from the injured compared with uninjured parietotemporal cortex, whereas comparable yields were obtained from the hippocampus. After injury, cortical and hippocampal tissue ATP concentrations declined significantly to 60% and 40% of control, respectively, in the absence of respiratory deficits in isolated mitochondria. Mitochondria with ultrastructural morphologic damage comprised a significantly greater percent of the population isolated from injured than uninjured brain. As determined by photon correlation spectroscopy, the mean mitochondrial radius decreased significantly in injured cortical populations (361 +/- 40 nm at 24 hours) and increased significantly in injured hippocampal populations (442 +/- 36 at 3 hours) compared with uninjured populations (Ctx: 418 +/- 44; Hipp: 393 +/- 24). Calcium-induced deenergized swelling rates of isolated mitochondrial populations were significantly slower in injured compared with uninjured samples, suggesting that injury alters the kinetics of mitochondrial permeability transition (MPT) pore activation. Cyclosporin A (CsA)-insensitive swelling was reduced in the cortex, and CsA-sensitive and CsA-insensitive swelling both were reduced in the hippocampus, demonstrating that regulated MPT pores remain in mitochondria isolated from injured brain. A proposed mitochondrial population model synthesizes these data and suggests that cortical mitochondria may be depleted after TBI, with a physically smaller, MPT-regulated population remaining. Hippocampal mitochondria may sustain damage associated with ballooned membranes and reduced MPT pore calcium sensitivity. The heterogeneous mitochondrial response to TBI may underlie posttraumatic metabolic dysfunction and contribute to the pathophysiology of TBI.},
  author       = {Lifshitz, J and Friberg, Hans and Neumar, RW and Raghupathi, R and Welsh, FA and Janmey, P and Saatman, KE and Wieloch, Tadeusz and Grady, MS and McIntosh, TK},
  issn         = {1559-7016},
  keyword      = {scatter,dynamic light,cell death,photon correlation spectroscopy,swelling,mitochondrial,head injury,mitochondrial permeability transition},
  language     = {eng},
  number       = {2},
  pages        = {219--231},
  publisher    = {Nature Publishing Group},
  series       = {Journal of Cerebral Blood Flow and Metabolism},
  title        = {Structural and functional damage sustained by mitochondria after traumatic brain injury in the rat: Evidence for differentially sensitive populations in the cortex and hippocampus},
  url          = {http://dx.doi.org/10.1097/00004647-200302000-00009},
  volume       = {23},
  year         = {2003},
}