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

    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

    Share

    COinS