Cytochrome c is released from mitochondria in a reactive oxygen species (ROS)-dependent fashion and can operate as a ROS scavenger and as a respiratory substrate in cerebellar neurons undergoing excitotoxic death
A. Atlante et al., Cytochrome c is released from mitochondria in a reactive oxygen species (ROS)-dependent fashion and can operate as a ROS scavenger and as a respiratory substrate in cerebellar neurons undergoing excitotoxic death, J BIOL CHEM, 275(47), 2000, pp. 37159-37166
In rat cerebellar granule cells both reactive oxygen species production and
release of cytochrome c take place during glutamate toxicity. This investi
gation was aimed (i) to ascertain whether and how these two processes are r
elated and (ii) to gain insight into the role played by the released cytoch
rome c in the onset of neurotoxicity. Cytochrome c release takes place owin
g to the generation of reactive oxygen species both in glutamate-treated ce
rebellar granule cells and in sister control cultures incubated in the pres
ence of the reactive oxygen species generating system consisting of xanthin
e plus xanthine oxidase. In the early phase of neurotoxicity (30-min glutam
ate exposure) about 40% of the maximum las measured at 3 h of glutamate exp
osure) cytochrome c release was found to occur in cerebellar granule cells
from mitochondria that were essentially coupled and intact and that had a n
egligible production of oxygen free radicals. Contrarily, mitochondria from
cells treated with glutamate for 3 h were mostly uncoupled and produced re
active oxygen species at a high rate. The cytosolic fraction containing the
released cytochrome c was able to transfer electrons from superoxide anion
to molecular oxygen via the respiratory chain and was found to partially p
revent glutamate toxicity when added externally to cerebellar neurons under
going necrosis. In the light of these findings, we propose that in the earl
y phase of neurotoxicity, cytochrome c release can be part of a cellular an
d mitochondrial defense mechanism against oxidative stress.