Uncoupling protein 2 prevents neuronal death including that occurring during seizures: a mechanism for preconditioning.
The mitochondrial uncoupling protein (UCP2) is expressed in selected regions of the brain. Here we demonstrate that up-regulation of UCP2 is part of a neuroprotective set of responses to various cellular stresses in vitro and in vivo. PC12 cells, when transfected with UCP2, were protected against free radical-induced cell death. Seizure activity was associated with elevated UCP2 levels and mitochondrial uncoupling activity. In transgenic mice that expressed UCP2 constitutively in the hippocampus before seizure induction, a robust reduction in cell death was seen. Because UCP2 increased mitochondrial number and ATP levels with a parallel decrease in free radical-induced damage, it is reasonable to suggest that mitochondrial UCPs precondition neurons by dissociating cellular energy production from that of free radicals to withstand the harmful effects of cellular stress occurring in a variety of neurodegenerative disorders, including epilepsy.
Diano
Sabrina
S
Department of Obstetrics and Gynecology, Yale Medical School, 333 Cedar Street, New Haven Connecticut 06520, USA.
Matthews
Russell T
RT
Patrylo
Peter
P
Yang
Lichuan
L
Beal
M Flint
MF
Barnstable
Colin J
CJ
Horvath
Tamas L
TL
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004827:Epilepsy / Q000503:physiopathology*; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007473:Ion Channels; D015227:Lipid Peroxidation / Q000187:drug effects; D026901:Membrane Transport Proteins; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D024101:Mitochondrial Proteins; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects; D011506:Proteins / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D000071246:Uncoupling Protein 2
D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D011506:Proteins; D012333:RNA, Messenger; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate