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

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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.

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Abbreviations

3-NP:

3-nitropropionic acid

BAPTA-AM:

(5,5- dimethyl bis-(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic)-acetoxymethylester

6-NMDG:

6-(N-(7 nirobenz0-2-oxa-1-3-diazol-4-yl) amino-6-deoxy-glucose

BDNF:

Brain-derived neurotrophin factor

CREB:

cAMP-responsive element-binding

DNP:

2,4-dinitrophenol

EGF:

Epidermal growth factor

ERK:

Extracellular signal-regulated kinase

Glut1:

Glucose transporter 1

Hif-1α:

Hypoxia-inducible factor-1α

LDH:

Lactate dehydrogenase

MAPK:

Mitogen-activated protein kinase

NGF:

Nerve growth factor

SAPK/JNK:

Stress-activated protein kinase/c-Jun NH2-terminal kinase

ROS:

Reactive oxygen species

TrkA:

Tropomyosin-Related Kinase A

UCP:

Uncoupling protein

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  1. Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4000 Central Florida Blvd, Orlando, FL, 32816, USA

    Zelan Wei, Srinivasulu Chigurupati, Pamela Bagsiyao, Alicia Henriquez & Sic L. Chan

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  1. Zelan Wei
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  2. Srinivasulu Chigurupati
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  3. Pamela Bagsiyao
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  4. Alicia Henriquez
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  5. Sic L. Chan
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Correspondence to Sic L. Chan.

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Wei, Z., Chigurupati, S., Bagsiyao, P. et al. 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, 14–29 (2009). https://doi.org/10.1007/s12640-009-9039-8

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