Role of brain uncoupling proteins in energy homostasis and oxygen radical metabolism

Neurons have an extremely high rate of energy consumption and use mitochondrial-derived ATP as the primary energy source to drive biochemical processes involved in various functions. Consequently, neurons produce reactive oxygen species (ROS) as \u27by-products\u27 of oxidative phosphorylation. Excessive levels of ROS are highly detrimental to neurons as ROS can directly oxidize and induce damage to cellular macromolecules including lipids, DNA and proteins. Hence, the high-energy demands of neurons, together with their high levels of ROS production, place them at risk during conditions of stress, which occur during aging and in neurodegenerative disorders including Alzheimer\u27s and Huntington\u27s disease. Uncoupling proteins (UCPs) belong to a family of inner mitochondrial membrane proteins initially identified as regulators of thermogenesis in fat cells wherein they uncouple energy-substrate oxidation from mitochondrial ATP production, resulting in the production of heat. UCPs also regulate ROS production from mitochondria by physiologically lowering the mitochondrial membrane potential below the critical level for ROS production. Because of their important role in co-regulating energy metabolism and ROS production, there has been considerable interest in the functions of UCPs. Neurons express at least three UCPs including the widely expressed UCP2 and the brain- specific UCP4 and UCP5. Despite a great deal of interest, to date neither the molecular mechanism nor the biochemical and physiological functions of brain UCPs are well understood. Our previous studies showed that UCP4 is highly expressed in subpopulations of neurons with high energy demands. Knockdown ofUCP4 expression in cultured primary neurons markedly enhances neuronal death suggesting that endogenous UCP4 is critical for neuronal survival. Expression of UCP4 shifts cellular ATP synthesis from oxidative phosphorylation to anaerobic glycolysis, which might be beneficial to cell survival. In this study, we investigated the underlying mechanism of UCP4-mediated metabolic adaptation in response to mitochondrial inhibition. We found that UCP4 enhances glucose uptake and glycolysis which may compensate for the reduced supply of ATP from compromised mitochondria. In addition, the activation of mitogen activated protein kinases (MAPKs) and several transcription factors play a role in augmenting nonoxidative synthesis of ATP in response to metabolic stress possibly by acting downstream of UCP4. Elucidating the underlying mechanism(s) whereby this brain UCP mediates metabolic adaptation in response to mitochondrial inhibition will likely lead to the development of novel preventative and therapeutic strategies for neurodegenerative disorders

The Brain Uncoupling Protein Ucp4 Attenuates Mitochondrial Toxin-Induced Cell Death: Role Of Extracellular Signal-Regulated Kinases In Bioenergetics Adaptation And Cell Survival

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. © Springer Science+Business Media, LLC 2009