Oxidative stress-dependent release of mitochondrial cytochrome c after traumatic brain injury

Mitochondrial cytochrome c translocation to the cytosol initiates the mitoc hondrial-dependent apoptotic pathway. This event has not been previously re ported in traumatic; brain injury (TBI). The authors determined the express ion of cytochrome c in cytosolic and mitochondrial fractions after severe T BI produced by the controlled cortical impact model in the mouse. One hour after trauma there was an increase in cytosolic cytochrome c immunoreactivi ty. The increases in cytosolic cytochrome c preceded DNA fragmentation, whi ch started at 4 hours. Western blots of mitochondrial and cytosolic fractio ns confirmed that there was a translocation of cytochrome c from the mitoch ondria after TBI. Mice deficient in manganese superoxide dismutase (MnSOD) showed an increased loss of mitochondrial cytochrome c after trauma, but le ss 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 s how that cytochrome c is released from the mitochondria after severe TBI pa rtly by a free radical-dependent mechanism, and that massive mitochondrial cytochrome c release is a predictor of necrotic cell death rather than apop tosis.