Title

The Brain Uncoupling Protein UCP4 Attenuates Mitochondrial Toxin-Induced Cell Death: Role of Extracellular Signal-Regulated Kinases in Bioenergetics Adaptation and Cell Survival

Authors

Authors

Z. L. Wei; S. Chigurupati; P. Bagsiyao; A. Henriquez;S. L. Chan

Abbreviated Journal Title

Neurotox. Res.

Keywords

Glycolysis; Mitochondrial uncoupling protein; Energy metabolism; OXYGEN SPECIES PRODUCTION; PREVENTS NEURONAL DEATH; NERVE GROWTH-FACTOR; HUNTINGTONS-DISEASE; OXIDATIVE STRESS; NEUROTROPHIC FACTOR; ANAEROBIC; GLYCOLYSIS; ENERGY-METABOLISM; 3-NITROPROPIONIC ACID; STRIATAL; DEGENERATION; Neurosciences

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.

Journal Title

Neurotoxicity Research

Volume

16

Issue/Number

1

Publication Date

1-1-2009

Document Type

Article

Language

English

First Page

14

Last Page

29

WOS Identifier

WOS:000266010600002

ISSN

1029-8428

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