Uncoupling protein-2 accumulates rapidly in the inner mitochondrial membrane during mitochondrial reactive oxygen stress in macrophages

Giardina, Tindaro; Steer, James H.; Lo, Susan; Joyce, David A.

doi:10.1016/j.bbabio.2007.11.006

Cited by 68 publications

(53 citation statements)

References 329 publications

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“…In absence of appropriate mitochondrial uncoupling, a physiological stimulus such as exercise that normally promotes positive brain plasticity can, in fact, result in a deleterious effect, perhaps because of increased production of free radicals. UCP2 has been shown to be a radical scavenger (Echtay et al, 2002;Produit-Zengaffinen et al, 2007;Giardina et al, 2008), which is one of the likely mechanisms via which UCP2 can exert a protective effect on cellular and synaptological adaptations to increased workload on hippocampal neuron triggered by increased voluntary exercise.…”

Section: Discussionmentioning

confidence: 99%

Exercise-Induced Synaptogenesis in the Hippocampus Is Dependent on UCP2-Regulated Mitochondrial Adaptation

Dietrich¹,

Andrews²,

Horváth³

2008

J. Neurosci.

141

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Mitochondria are essential organelles in neurons providing appropriate energetic needs to maintain resting and action potentials as well as to modulate synaptic plasticity. Although neuronal events underlie various behavioral events, the behavior itself, such as voluntary exercise, feeds back to affect neuronal morphology and function as well as glial morphology and function. The hippocampal formation is a main site of synaptic plasticity induced by voluntary exercise. Here we show that voluntary exercise induces uncoupling protein 2 (UCP2) mRNA expression and mitochondrial oxygen consumption in coupled as well as uncoupled respiratory states in the hippocampus. These changes in mitochondrial metabolism coincided with an increase in mitochondrial number and dendritic spine synapses in granule cells of the dentate gyrus and the stratum radiatum of the CA1 region and were dependent on UCP2 expression, because in UCP2 knock-out mice such changes were not observed. Together, these observations reveal that a mitochondrial mechanism related to UCP2 function is essential for appropriate bioenergetic adaptation of neurons to increased neuronal activity and synaptic plasticity in response to exercise.

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Section: Discussionmentioning

confidence: 99%

Exercise-Induced Synaptogenesis in the Hippocampus Is Dependent on UCP2-Regulated Mitochondrial Adaptation

Dietrich¹,

Andrews²,

Horváth³

2008

J. Neurosci.

141

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“…Although the uncoupling activity of uncoupling proteins may be dependent on acute regulation by endogenous activators such as protonmotive force, fatty acids and reactive alkenals [17,18,20], it is not known whether, or how, such activation is acutely reversed [35]. A plausible mechanism of deactivation of any postulated function of UCP2 is by protein degradation: in ovarian and granulosa cell lines and in macrophages, UCP2 is turned over remarkably rapidly, with a half-life of about 1 h [36,37]. The same is true in INS-1E cells, where the half-life is constant at about 60 min, regardless of the glucose concentration and putative activation state [12].…”

Section: Dynamic Regulation Of Ucp2 Concentration In Pancreatic β-Cellsmentioning

confidence: 99%

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

Brand

Parker

Affourtit

et al. 2010

Diabetes Obesity Metabolism

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Pancreatic β-cells have remarkable bioenergetics in which increased glucose supply upregulates the cytosolic ATP/ADP ratio and increases insulin secretion. This arrangement allows glucose-stimulated insulin secretion (GSIS) to be regulated by the coupling efficiency of oxidative phosphorylation. Uncoupling protein 2 (UCP2) modulates coupling efficiency and may regulate GSIS. Initial measurements of GSIS and glucose tolerance in Ucp2 −/− mice supported this model, but recent studies show confounding effects of genetic background. Importantly, however, the enhancement of GSIS is robustly recapitulated with acute UCP2 knockdown in INS-1E insulinoma cells. UCP2 protein level in these cells is dynamically regulated, over at least a fourfold concentration range, by rapid proteolysis (half-life less than 1 h) opposing regulated gene transcription and mRNA translation. Degradation is catalysed by the cytosolic proteasome in an unprecedented pathway that is currently known to act only on UCP2 and UCP3. Evidence for proteasomal turnover of UCP2 includes sensitivity of degradation to classic proteasome inhibitors in cells, and reconstitution of degradation in vitro in mitochondria incubated with ubiquitin and the cytosolic 26S proteasome. These dynamic changes in UCP2 content may provide a fine level of control over GSIS in β-cells. Keywords: glucose-stimulated insulin secretion, INS-1E cells, mitochondria, proteasome, protein degradation, turnover, UCP2, UCP3 Date submitted 25 March 2010; date of final acceptance 24 April 2010 IntroductionThe energy metabolism of pancreatic β-cells is extraordinary. Nearly all other mammalian cells rigorously regulate their bioenergetics using internal cues, and only take up fuels when they need them for oxidation and energy release or for storage. Pancreatic β-cells work the other way round, and use fuel supply to regulate their ATP production and cytosolic ATP/ADP ratio.A skeletal muscle cell, for example, will take up glucose from the bloodstream through a plasma membrane glucose transporter, glucose transporter type 4 (GLUT4), when insulin is high and glucose is abundant, otherwise it will use fatty acids as fuel [1]. It will store glucose as glycogen when insulin and ATP are high and calcium (the trigger for muscle contraction and energy demand) is low. Even after glucose enters the cytoplasm, a muscle cell will allow it to enter glycolysis only when that cell requires energy. Glucose 6-phosphate is a non-competitive inhibitor of muscle hexokinase, so when ATP is sufficiently high, glycolysis stalls, glucose 6-phosphate builds up, hexokinase activity is inhibited and glucose metabolism slows. When more ATP is needed because of internal ATP demand, phosphofructokinase and pyruvate kinase are activated, glucose 6-phosphate levels fall and hexokinase channels glucose into glycolysis and to the mitochondria. The mitochondrial electron transport chain pumps protons across the mitochondrial inner membrane, restoring a high protonmotive force and ATP production, until ATP rises and oxidativ...

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“…However, in conjunction with its uncoupling function, UCP2 is also thought to mediate mitochondrial ROS production. Several recent studies have demonstrated that UCP2 acts as a modulator of ROS production in various tissues (Anedda et al 2008, Degasperi et al 2008, Giardina et al 2008. Interestingly, UCP2 has been shown to be activated by ROS molecules themselves (Echtay et al 2002, Krauss et al 2003, potentially representing a feedback loop whereby UCP2 senses mitochondrial ROS and upregulates its expression in an attempt to decrease high ROS production (Giardina et al 2008).…”

Section: Knockout Of Ucp2 Impairs A-cell Function and Contributes To mentioning

confidence: 99%

Uncoupling protein 2 regulates reactive oxygen species formation in islets and influences susceptibility to diabetogenic action of streptozotocin

Lee

Doucette²,

Wheeler³

2009

Journal of Endocrinology

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Currently, the physiological function of uncoupling protein-2 (UCP2) in pancreatic islets and its role in the development of diabetes is a matter of great debate. To further investigate the impact of UCP2 on diabetes development, we used streptozotocin (STZ) to experimentally generate diabetes in both wild-type (WT) and UCP2-knockout (UCP2KO) mice. While multiple low-dose STZ injections led to hyperglycemia development over a 14-day period in both WT and UCP2KO mice, we found the development of hyperglycemia to be significantly less severe in the UCP2KO mice. Measurement of insulin and glucagon secretion (in vitro), as well as their plasma concentrations (in vivo), indicated that UCP2-deficiency showed enhanced insulin secretion but impaired a-cell function. Glucagon secretion was attenuated, despite reduced insulin secretion after exposure to STZ, which together contributed to less severe hyperglycemia development in UCP2KO mice. Further experimentation revealed that UCP2-deficient a-and b-cells had chronically higher cellular reactive oxygen species (ROS) levels than the WT prior to STZ application, which correlated with increased basal b-and a-cell mass. Overall, we suggest that increased chronic ROS signaling as a result of UCP2-deficiency contributes to enhanced b-cell function and impairment of a-cell function, leading to an attenuation of STZ-induced hyperglycemia development.

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Uncoupling protein-2 accumulates rapidly in the inner mitochondrial membrane during mitochondrial reactive oxygen stress in macrophages

Cited by 68 publications

References 329 publications

Exercise-Induced Synaptogenesis in the Hippocampus Is Dependent on UCP2-Regulated Mitochondrial Adaptation

Exercise-Induced Synaptogenesis in the Hippocampus Is Dependent on UCP2-Regulated Mitochondrial Adaptation

Mitochondrial uncoupling protein 2 in pancreatic β‐cells

Uncoupling protein 2 regulates reactive oxygen species formation in islets and influences susceptibility to diabetogenic action of streptozotocin

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