The brain uncoupling protein UCP4 attenuates mitochondrial toxin-induced cell death: role of extracellular signal-regulated kinases in bioenergetics adaptation and cell survival.
Neurotox Res
; 16(1): 14-29, 2009 Jul.
Article
en En
| MEDLINE
| ID: mdl-19526295
ABSTRACT
Increased bioenergetics demand can stimulate compensatory increases in glucose metabolism. We previously reported that neural cells expressing the brain uncoupling protein UCP4 exhibit enhanced dependency on glucose for support of cellular bioenergetics and survival. The switch from oxidative toward glycolytic metabolism reduces the production of toxic reactive oxygen species (ROS) and increases cellular resistance to toxicity induced by 3-nitropropionic acid, a mitochondrial complex II inhibitor that compromises cellular bioenergetics. In this study we elucidate the underlying mechanism whereby expression of UCP4 promotes bioenergetics adaptation and cell survival. We found that activation of extracellular signal-regulated kinases (ERKs) is necessary and sufficient for the increased dependency on glucose utilization. Pharmacological inhibition of ERKs not only abrogated bioenergetics adaptation but also reduced the activation of cAMP-responsive element-binding (CREB) protein suggesting that CREB protein signaling contributes in part to UCP4-dependent cell death rescue from 3-nitropropionic acid-induced toxicity. We also demonstrated that activation of ERKs by growth factors ameliorated the bioenergetics compromise and reduced cellular toxicity induced by 3-nitropropionic acid. Collectively, our results support the involvement of ERKs in UCP4 dependent bioenergetics adaptation and cell survival.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Proteínas de Transporte de Membrana
/
Propionatos
/
Quinasas MAP Reguladas por Señal Extracelular
/
Metabolismo Energético
/
Neuronas
/
Neurotoxinas
/
Nitrocompuestos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Neurotox Res
Asunto de la revista:
NEUROLOGIA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos