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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.

J. Neurochem. (2010) 114, 323–334. Because the olfactory system plays a major role in food consumption, and because ‘food addiction’ and associated morbidities have reached epidemic proportions, we tested the hypothesis that dietary energy restriction can modify adverse effects of cocaine on behavior and olfactory cellular and molecular plasticity. Mice maintained on an alternate day fasting (ADF) diet exhibited increased baseline locomotion and increased cocaine-sensitized locomotion during cocaine conditioning, despite no change in cocaine conditioned place preference, compared with mice fed ad libitum. Levels of dopamine and its metabolites in the olfactory bulb (OB) were suppressed in mice on the ADF diet compared with mice on the control diet, independent of acute or chronic cocaine treatment. The expression of several enzymes involved in dopamine metabolism including tyrosine hydroxylase, monoamine oxidases A and B, and catechol-O-methyltransferase were significantly reduced in OBs of mice on the ADF diet. Both acute and chronic administration of cocaine suppressed the production of new OB cells, and this effect of cocaine was attenuated in mice on the ADF diet. Cocaine administration to mice on the control diet resulted in up-regulation of OB genes involved in mitochondrial energy metabolism, synaptic plasticity, cellular stress responses, and calcium- and cAMP-mediated signaling, whereas multiple olfactory receptor genes were down-regulated by cocaine treatment. ADF abolished many of the effects of cocaine on OB gene expression. Our findings reveal that dietary energy intake modifies the neural substrates underlying some of the behavioral and physiological responses to repeated cocaine treatment, and also suggest novel roles for the olfactory system in addiction. The data further suggest that modification of dietary energy intake could provide a novel potential approach to addiction treatments. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondrial dysfunction and reactive oxygen species (ROS) production are at the heart of the aging process and are thought to underpin age-related diseases. Mitochondria are not only the primary energy-generating system but also the dominant cellular source of metabolically derived ROS. Recent studies unravel the existence of mechanisms that serve to modulate the balance between energy metabolism and ROS production. Among these is the regulation of proton conductance across the inner mitochondrial membrane that affects the efficiency of respiration and heat production. The field of mitochondrial respiration research has provided important insight into the role of altered energy balance in obesity and diabetes. The notion that respiration and oxidative capacity are mechanistically linked is making significant headway into the field of aging and age-related diseases. Here we review the regulation of cellular energy and ROS balance in biological systems and survey some of the recent relevant studies that suggest that respiratory adaptation and thermodynamics are important in aging and age-related diseases. [Copyright &y& Elsevier]