Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death.
Excitotoxic cell death is the fundamental process responsible for many human neurodegenerative disorders, yet the basic mechanisms involved are not fully understood. Here, we exploited the fact that the immature brain is remarkably resistant to seizure-induced excitotoxic cell death and examined the underlying protective mechanisms. We found that, unlike in the adult, seizures do not increase the formation of reactive oxygen species or result in mitochondrial dysfunction in neonatal brain, because of high levels of the mitochondrial uncoupling protein (UCP2). UCP2 expression and function were basally increased in neonatal brain by the fat-rich diet of maternal milk, and substituting a low-fat diet reduced UCP2, restored mitochondrial coupling, and permitted seizure-induced neuronal injury. Thus, modulation of UCP2 expression and function by dietary fat protects neonatal neurons from excitotoxicity by preventing mitochondrial dysfunction. This mechanism offers novel neuroprotective strategies for individuals, greater than 1% of the world's population, who are affected by seizures.
Sullivan
Patrick G
PG
Department of Neurobiology and Behavior, University of California at Irvine, Irvine, CA 92697-4475, USA.
Dubé
Celine
C
Dorenbos
Kristina
K
Steward
Oswald
O
Baram
Tallie Z
TZ
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D007473:Ion Channels; D007608:Kainic Acid / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D011506:Proteins / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2
D000906:Antibodies; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D009498:Neurotoxins; D011506:Proteins; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; C000604391:Ucp2 protein, rat; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D007608:Kainic Acid