title: The brain uncoupling protein UCP4 attenuates mitochondrial toxin-induced cell death: role of extracellular signal-regulated kinases in bioenergetics adaptation and cell survival.
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.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4000 Central Florida Blvd, Orlando, FL 32816, USA.
authors.forename: Zelan
authors.initials: Z
authors.lastname: Wei
authors.forename: Srinivasulu
authors.initials: S
authors.lastname: Chigurupati
authors.forename: Pamela
authors.initials: P
authors.lastname: Bagsiyao
authors.forename: Alicia
authors.initials: A
authors.lastname: Henriquez
authors.forename: Sic L
authors.initials: SL
authors.lastname: Chan
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004622:Embryo, Mammalian; D004734:Energy Metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000071245:Mitochondrial Uncoupling Proteins; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds / Q000633:toxicity*; D016716:PC12 Cells; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D002614:Chelating Agents; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D000071245:Mitochondrial Uncoupling Proteins; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; C117577:SLC25A27 protein, human; D004533:Egtazic Acid; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D020932:Nerve Growth Factor; D050882:CREB-Binding Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C015392:3-nitropropionic acid