Oxidative stress-dependent release of mitochondrial cytochrome c after traumatic brain injury.
Mitochondrial cytochrome c translocation to the cytosol initiates the mitochondrial-dependent apoptotic pathway. This event has not been previously reported in traumatic brain injury (TBI). The authors determined the expression of cytochrome c in cytosolic and mitochondrial fractions after severe TBI produced by the controlled cortical impact model in the mouse. One hour after trauma there was an increase in cytosolic cytochrome c immunoreactivity. The increases in cytosolic cytochrome c preceded DNA fragmentation, which started at 4 hours. Western blots of mitochondrial and cytosolic fractions confirmed that there was a translocation of cytochrome c from the mitochondria after TBI. Mice deficient in manganese superoxide dismutase (MnSOD) showed an increased loss of mitochondrial cytochrome c after trauma, but less apoptotic cell death 4 and 24 hours after injury compared with wild-type control mice. However, the overall cell death was increased in MnSOD mice, as illustrated by a larger cortical lesion in these animals. The results show that cytochrome c is released from the mitochondria after severe TBI partly by a free radical-dependent mechanism, and that massive mitochondrial cytochrome c release is a predictor of necrotic cell death rather than apoptosis.
Lewén
A
A
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305-5487, USA.
Fujimura
M
M
Sugawara
T
T
Matz
P
P
Copin
J C
JC
Chan
P H
PH
D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D003574:Cytochrome c Group / Q000378:metabolism*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress
D003574:Cytochrome c Group