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Keywords:

  • uncoupling protein;
  • mitochondria;
  • carrier;
  • glucose and fatty acid oxidation;
  • metabolism

Abstract

  1. Top of page
  2. Abstract
  3. HISTORY OF THE FIRST UNCOUPLING PROTEIN, UCP1
  4. UCP2, A SINGULAR PROTEIN AMONG THE UNCOUPLING PROTEINS
  5. DO THE NEW UCPS EVEN HAVE UNCOUPLING ACTIVITY?
  6. UCP2 AS A METABOLIC SENSOR OR REGULATOR
  7. COULD PYRUVATE EXPORT EXPLAIN THE UCP2−/− MICE PHENOTYPES?
  8. CONCLUSION
  9. REFERENCES

Mitochondrial uncoupling of oxidative phosphorylation may serve a variety of purposes such as the regulation of substrate oxidation, free radical production (a major by-product of mitochondrial respiration) and ATP production and turnover. As regulators of energy expenditure and antioxidant defenses, uncoupling proteins would seem to offer an attractive mechanism by which to explain the control of body weight, resting metabolic rate and aging. As a result, the discovery of UCP1 homologues has led to an impressive number of publications. However, 10 years after their identification, no consensus has been found concerning the function of UCP homologues, and there are controversies as to whether or not they even have physiologically significant uncoupling activity. Here, we discuss a potential new function for UCP2, as a carrier involved in the coupling between glucose oxidation and mitochondrial metabolism. © 2009 IUBMB IUBMB Life 61(7): 762–767, 2009


HISTORY OF THE FIRST UNCOUPLING PROTEIN, UCP1

  1. Top of page
  2. Abstract
  3. HISTORY OF THE FIRST UNCOUPLING PROTEIN, UCP1
  4. UCP2, A SINGULAR PROTEIN AMONG THE UNCOUPLING PROTEINS
  5. DO THE NEW UCPS EVEN HAVE UNCOUPLING ACTIVITY?
  6. UCP2 AS A METABOLIC SENSOR OR REGULATOR
  7. COULD PYRUVATE EXPORT EXPLAIN THE UCP2−/− MICE PHENOTYPES?
  8. CONCLUSION
  9. REFERENCES

One of the major roles of mitochondria is the production of ATP via the coupling between the electron transport chain and oxidative phosphorylation. Energy sources such as glucose and fatty acids are initially metabolized in the cytoplasm. The products are imported via specific carriers into mitochondria where their catabolism will continue using different metabolic pathways including beta oxidation and amino acid oxidation. The end result of these different pathways is the production of 2 energy-rich electron donors, NADH and FADH2. Electrons from these molecules will then enter the electron transport chain and spontaneously go through a succession of redox reactions allowing the final reduction of oxygen to water. Simultaneously, the enzymes involved in these redox reactions are pumping protons creating an electrochemical force used by the F0F1-ATPase to produce ATP.

It was known that mitochondria from brown adipose tissue (BAT) exhibit a significant permeability to protons, allowing them to produce heat [review in (1)]. Based on these results, it was proposed that a specific protein was responsible for this abnormal ion conductance across the membrane, leading to the identification of the first uncoupling protein, UCP1 (2). In brown adipocytes, the presence of UCP1 creates an alternative way for protons to return to the mitochondrial matrix, leading to uncoupled mitochondrial respiration; that is, the electron transport chain is no longer coupled to ATP synthesis. As a result, energy from redox reactions is released as heat instead of used to produce ATP. The physiological role of UCP1 in nonshivering thermogenesis has been well established since by several research groups. The importance of UCP1 in cold-induced thermogenesis was confirmed in 1997 with the gene invalidation in mice by the laboratory of Leslie Kozak, because Ucp1−/− mice were unable to maintain their body temperature during cold exposure (3).

It is apparent that such protein cannot be constitutively active and its activity must be tightly regulated in accordance to the thermogenic needs of the animals. In fact, UCP1 activity is inhibited by purine nucleotides (4). When exposed to cold, a signal is transmitted via the sympathetic nervous system to brown adipocytes, resulting in increased UCP1 expression and activity (4, 5). Interestingly, fatty acids directly activate UCP1 and are the substrate for thermogenesis via beta oxidation. However, the precise substrate of UCP1—postulated to be either protons transported into the mitochondrial matrix, or fatty acid anions transported out of it—is as yet unclear (6, 7).

UCP2, A SINGULAR PROTEIN AMONG THE UNCOUPLING PROTEINS

  1. Top of page
  2. Abstract
  3. HISTORY OF THE FIRST UNCOUPLING PROTEIN, UCP1
  4. UCP2, A SINGULAR PROTEIN AMONG THE UNCOUPLING PROTEINS
  5. DO THE NEW UCPS EVEN HAVE UNCOUPLING ACTIVITY?
  6. UCP2 AS A METABOLIC SENSOR OR REGULATOR
  7. COULD PYRUVATE EXPORT EXPLAIN THE UCP2−/− MICE PHENOTYPES?
  8. CONCLUSION
  9. REFERENCES

Mitochondrial carriers are responsible for the exchange of essential metabolites such as pyruvate, mono-, di-, and tri-carboxylates, or ADP and ATP between the cytoplasm and the mitochondria. To date, around 30 carriers have been identified. All these proteins share common features such as a molecular weight around 30 kD, a protein sequence organized as tandem repeats of ∼100 amino acids, each consisting of two transmembrane domains and a signature motif specific to proteins belonging to this family. Among the mitochondrial carriers, a subgroup of proteins has emerged in the past 10 years, the uncoupling proteins (UCP). UCP2 and UCP3 were identified in 1997 (8, 9). Both proteins share nearly 55% of identity with UCP1 while being 80% homologous to each other. Both Ucp2 and Ucp3 genes are adjacent and localized on chromosome 11 in humans and chromosome 7 in mice. Interestingly, this genomic region is associated with hyperinsulinemia and obesity (9). Later, UCP4 (10) and BMCP1/UCP5 (11) were cloned; however, their categorization to the subfamily of uncoupling proteins is controversial because they exhibit the same degree of homology toward UCP1, UCP2, and UCP3 as they do to other mitochondrial carriers.

UCP2 exhibits singular features which distinguish it from other mitochondrial carriers, including UCP1:

  • 1
    UCP2 mRNA is found in many tissues (9) whereas UCP1, UCP3, UCP4, and BMCP1 mRNA are mainly expressed in brown adipocytes, muscle and brain, respectively (8, 10–12).
  • 2
    UCP2 is regulated at both the transcriptional (13–16) and the translational level (17–19). The presence of an open reading frame upstream of the one coding UCP2 exerted a constitutive inhibition of UCP2 translation. As a direct consequence of this inhibition, the protein is present in very low abundance, less than 1% relative to UCP1 in BAT, and can only be detected in steady state in tissues with high mRNA level such as spleen, thymus, lung, pancreas, digestive tract and the immune cells. As a result, a majority of antibodies raised against the protein were not able to detect UCP2 in vivo, resulting in misleading interpretations. The inhibition of UCP2 translation can be relieved in vitro by the addition of glutamine and in vivo by fasting or an inflammatory state.
  • 3
    The half life of the protein is unusually short, around 30 minutes (20), making UCP2 a suitable candidate for regulating rapid biological responses. Although it has not been investigated thoroughly, it is commonly accepted that the half-life of other mitochondrial carriers is at least over 10 hours.

Early attempts to deduce UCP2 functions were based largely on the high sequence homology of this protein with UCP1, consequently assuming a similar physiological role, notably in energy expenditure. However, Ucp2−/− mice are not obese, even when fed on a high fat diet, and are resistant to cold exposure. In agreement with the genetic linkage, Ucp2−/− mice exhibit a hyperinsulinemic hypoglycemia (21). Hyperinsulinism was associated to an increased cellular ATP/ADP ratio in beta cells leading to the closure of the ATP-dependent K-channel and the subsequent opening of the voltage-dependent Ca-channel involved in insulin secretion. Our group showed that Ucp2−/− mice were resistant to the parasitic infection Toxoplasma gondii (22), which appears to be related to the greater capacity of macrophages to generate ROS and resist infection. Given the involvement of oxidative stress and immune response in various diseases, several groups including ours tested the hypothesis that UCP2 might be involved in chronic inflammatory or autoimmune diseases. Multiple sclerosis is characterized by myelin and neuronal degeneration following a long period of chronic inflammation. A well-characterized mouse model of multiple sclerosis is experimental autoimmune encephalomyelitis, in which mice are inoculated with myelin basic protein that results in CNS inflammation. Ucp2−/− mice develop more severe disease than their wild-type littermates in this system (23). Furthermore, Ucp2−/− mice or irradiated LDL-R-deficient mice transplanted with bone marrow from Ucp2−/− mice displayed bigger and more unstable atherosclerotic plaques when fed on a high fat diet than control mice (24, 25). Consistent with a role for Ucp2 in autoimmune-mediated disease, induction of type I diabetes by injection of low-dose streptozotocin occurred faster in Ucp2−/− mice compared to wild-type controls (26). Finally, Ucp2−/− mice are protected against cerebral ischemia following middle cerebral artery occlusion (27), whereas overexpression of UCP2 in the brain prevents seizure or stroke by decreasing neuronal death (28, 29).

DO THE NEW UCPS EVEN HAVE UNCOUPLING ACTIVITY?

  1. Top of page
  2. Abstract
  3. HISTORY OF THE FIRST UNCOUPLING PROTEIN, UCP1
  4. UCP2, A SINGULAR PROTEIN AMONG THE UNCOUPLING PROTEINS
  5. DO THE NEW UCPS EVEN HAVE UNCOUPLING ACTIVITY?
  6. UCP2 AS A METABOLIC SENSOR OR REGULATOR
  7. COULD PYRUVATE EXPORT EXPLAIN THE UCP2−/− MICE PHENOTYPES?
  8. CONCLUSION
  9. REFERENCES

There has been a growing debate as to whether UCP2, despite its name, even has any demonstrable uncoupling activity. Evidence which supports an uncoupling function for UCP2 includes its homology to UCP1, and increased respiration in yeast expressing the protein. Kidney mitochondria from mice lacking UCP2 are more “coupled” (30) and all Ucp2−/− mice phenotypes could potentially be explained by an uncoupling activity of UCP2 in vivo. The absence of an uncoupling protein would increase the mitochondrial membrane potential and as a result increased ROS production, probably at the level of complex III. Then, immune cells lacking UCP2 would produce more ROS and respond more readily to infection. They would also be responsible for a basal proinflammatory environment/state (31). In contrast, overexpression of UCP2 would confer protection against oxidative stress by decreasing ROS production. In beta cells, the absence of UCP2 would abolish any alternative pathway of proton return in the matrix (21, 30). As a result, the proton flux through the ATP synthase increases as well as the net production of ATP in the cells, resulting in closure of the ATP-dependent potassium channel located on the plasmic membrane. This leads to an opening of the potential-dependent Ca-channel and ultimately insulin secretion, and indeed Ucp2 −/− mice display enhanced glucose-stimulated insulin secretion.

However, there are also strong arguments against an uncoupling activity for UCP2. First, proton conductance has been shown in normal hepactocytes even though neither UCP2 nor another uncoupling protein have been detected in these cells under physiological conditions (32). Second, the cellular amount of UCP2 is so low that a physiologic uncoupling function seems questionable. Third, earlier observations of apparent in vitro uncoupling function for UCP2 have now been suggested to be an artifact of the experimental systems used (33, 34). Fourth, in tissues with mitochondria containing high levels of UCP2 such as spleen or lung, in either steady state or upon inflammation where UCP2 expression is increased, the uncoupling state of these cells does not differ between Ucp2−/− and wild-type cells (35). Fifth, the higher observed expression of UCP2 during fasting, a period of decreased energy use, does not support a primary role for this protein in energy dissipation (17, 36–38). Sixth, UCP2 appears to be highly expressed in cells and tissues with low amounts of mitochondria—tissues which rely more on glycolysis than oxidative phosphorylation for its energy production. Last but not least, as this protein was first described as an uncoupling protein, the early studies with Ucp2 did little to seek alternative explanations for its function.

UCP2 AS A METABOLIC SENSOR OR REGULATOR

  1. Top of page
  2. Abstract
  3. HISTORY OF THE FIRST UNCOUPLING PROTEIN, UCP1
  4. UCP2, A SINGULAR PROTEIN AMONG THE UNCOUPLING PROTEINS
  5. DO THE NEW UCPS EVEN HAVE UNCOUPLING ACTIVITY?
  6. UCP2 AS A METABOLIC SENSOR OR REGULATOR
  7. COULD PYRUVATE EXPORT EXPLAIN THE UCP2−/− MICE PHENOTYPES?
  8. CONCLUSION
  9. REFERENCES

In the past few years, an accumulating set of data, described below, convince us that the new UCPs should be considered as mitochondrial carriers rather than uncoupling proteins. In mouse embryonic fibroblasts, no difference in ROS production was observed between Ucp2−/− and wild-type cells, and the variation of the respiratory rate and the ATP/ADP ratio in these Ucp2−/− cells were inconsistent with an uncoupling function for UCP2 (39). In fact, the genetic loss of UCP2 leads to a faster proliferative rate associated with decreased mitochondrial fatty acid oxidation and increased glucose metabolism. The idea that UCP2 acts as a regulator of mitochondrial fatty acid oxidation is consistent with previous studies suggesting that UCP2 plays a role in lipid metabolism by promoting a shift from carbohydrate to lipid metabolism during fasting or by transporting free fatty acids out of mitochondria [review in (40)]. Interestingly, in our study, the presence of glucose in the media was not only sufficient but also required to observe such a difference, pointing out the importance of glucose metabolism in the proliferative phenotype. Other studies have shown a link between glucose metabolism and uncoupling proteins. Parton et al have shown that UCP2 negatively regulates glucose sensing in neurons and its absence prevents obesity-induced loss of glucose sensing (41). Studies performed with Ucp2−/− macrophages showed an impaired glutamine metabolism regardless of the mitochondrial coupling state (42). In fact, the flux of glutamine oxidation seems slower in the absence of UCP2, which in turn leads to the accumulation of metabolic intermediates such as aspartate and glutamate and limits the availability of reduced coenzymes for the respiratory chain. Interestingly, glutamine is also a potent enhancer of UCP2 translation (19). Glutamine is known to be an essential oxidative fuel in immune cells (43, 44). In these cells, whereas glucose is essentially converted to lactate, glutamine provides metabolic intermediates such as alphaketoglutarate for the TCA cycle. Glutamine and glucose are also the substrates preferentially consumed by fast-growth tumors cells (45). Most tumor cells have altered metabolism and rely primarily upon mitochondrial-independent sources of energy. The most well-known metabolic alteration in tumor cells, known as the Warburg effect, is an increased glycolytic capacity, even in the presence of oxygen. It is interesting to note that the absence of UCP2 triggers in the embryonic fibroblasts a metabolic switch similar to the one occurring in tumor cells.Interestingly, Ucp2−/− mice are more sensitive to colon tumor development induced by azoxymethane treatment (46). This phenotype was associated with an increased colon oxidative stress and NFkB activation. However, an increased glycolytic capacity could also contribute to carcinogenesis. A recent paper by Samudio et al suggested that the microenvironment of the tumor plays a role in the promotion or maintenance of the Warburg effect by decreasing the entry of pyruvate in the TCA cycle into leukemic cells (47) and UCP2 seems to play a role in this metabolic shift. Paradoxically, UCP2 expression is increased in tumor cells (48 and personal data). However, this observation is not that surprising considering that the glycolytic metabolism of tumor cells is driven by mutations that chronically enhanced signaling pathways such as PI3K/AKT/mTOR or transcription factors such as HIF1 alpha or Myc, independently of any physiologic constraints [for review, see (49)].

Glycolytic-derived pyruvate, fatty acids and glutamine are the main mitochondrial energetic fuels providing intermediates for the TCA cycle and reduced equivalents for the respiratory chain (Fig. 1). Interestingly the absence of UCP2 is associated with decreased fatty acid and glutamine oxidation, which provide AcetylCoA and OAA, respectively. In contrast, the oxidation of glucose is increased providing more pyruvate to the mitochondria. Pyruvate can then be converted to either AcetylCoA via pyruvate dehydrogenase or OAA via pyruvate decarboxylase. This suggests that UCP2 could play a role as a sensor for the choice of substrates supplying the TCA cycle. It has been shown that UCP1 is able to transport pyruvate (50, 51). It is thus tempting to imagine UCP2 as a carrier exporting pyruvate out from the mitochondria. In the absence of UCP2, pyruvate accumulation within mitochondria would provide enough intermediates to supply the TCA cycle and as a result fatty acid oxidation and/or glutamine oxidation would be decreased. Depending on the physiological conditions, expression/activation of UCP2 could either promote or limit mitochondrial pyruvate utilization. For example, during fasting where lipolysis and UCP2 expression is increased, pyruvate would be mostly exported, allowing the cell to spare glucose and the major mitochondrial bioenergetic substrate used will be fatty acids. In contrast, in tumor cells, the high glycolytic flux may exceed the Vmax of the pyruvate dehydrogenase (52) and increasing UCP2 expression in these condition may avoid pyruvate accumulation in the mitochondria. The translational inhibition of UCP2 combined with its short life could confer to the cell an easy way to rapidly modulate mitochondrial metabolism. Finally, as an ultimate checkpoint, one can imagine that UCP2 activity could also be controlled by the mitochondrial membrane potential, limiting the export of pyruvate if the mitochondria are not sufficiently polarized.

thumbnail image

Figure 1. Depending on nutrients availability, glucose or fatty acids, cells adjust their mitochondrial metabolism and use either glycolysis or mitochondrial oxidative phosphorylation to generate energy. In the absence of UCP2, cells convert their metabolism to glycolysis, which leads in turn to enhance their proliferation. In contrast, increasing UCP2 expression, for example during starvation, correlates with increased fatty acid oxidation while limiting glycolytic-derived pyruvate utilization. An export of pyruvate from mitochondria to the cytosol through UCP2 would be consistent with such effects.

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COULD PYRUVATE EXPORT EXPLAIN THE UCP2−/− MICE PHENOTYPES?

  1. Top of page
  2. Abstract
  3. HISTORY OF THE FIRST UNCOUPLING PROTEIN, UCP1
  4. UCP2, A SINGULAR PROTEIN AMONG THE UNCOUPLING PROTEINS
  5. DO THE NEW UCPS EVEN HAVE UNCOUPLING ACTIVITY?
  6. UCP2 AS A METABOLIC SENSOR OR REGULATOR
  7. COULD PYRUVATE EXPORT EXPLAIN THE UCP2−/− MICE PHENOTYPES?
  8. CONCLUSION
  9. REFERENCES

UCP2 as a carrier exporting pyruvate is consistent with its ubiquitous expression, especially in tissues with glycolytic metabolism, as well as its increase during fasting. Several enzymes involved in lipid metabolism such as cyclooxygenases or lipooxygenases are known to produce ROS as a by-product of their activities. It is also tempting to suggest that UCP2 could regulate ROS production as a secondary effect of its metabolic control rather than by directly uncoupling the mitochondrial respiration from ATP synthesis. It is essential for mitochondria to minimize superoxide production generated by the respiratory chain. For example, genetic ablation of the mitochondrial superoxide dismutase SOD2 is embryonic lethal and the SOD2+/− mice display increased oxidative stress (53). However, Ucp2−/− mice do not exhibit any developmental defects. Furthermore, the radicals utilized during phagocytosis are mostly generated by NADPH oxidase in immune cells (54) rather than by mitochondria. A glycolytic switch is advantageous for cell proliferation because glycolysis is able to produce ATP faster than oxidative phosphorylation and at the same time provide precursors for nucleic acids, lipids, and amino acids. The enhanced immune response as well as the increased sensitivity to atherosclerosis and autoimmune disease could be explained by such a glycolytic switch triggered by the absence of UCP2 in that enhanced proliferation, migration, and activation of immune cells could lead to these phenotypes. The enhanced glucose-stimulated insulin secretion phenotype observed in Ucp2−/− mice could also be explained by Ucp2 serving as a “metabolic switch”: high glycolytic flux leading to a decrease in cellular ADP level could induce the closure of the ATP dependent potassium channel and induce insulin secretion (55). Finally, it has been shown that the inverse relationship between the use of fatty acid and carbohydrate is important in the clinical setting of ischemia in the heart (56). Several studies have shown that altering energy metabolism pharmacologically to either decrease fatty acid oxidation or increase glucose oxidation can improve the recovery after an ischemia. Furthermore, if glucose oxidation is increased during reperfusion, cardiac recovery is improved by increasing the efficiency to convert energy into contractile function. Neurons are analogous to cardiac myocytes in that they are also characterized by high energy demands to support their electrochemical activity. This high-metabolic load on mitochondria places this cell type at risk for energy failure, oxidative damage and cell death during ischemia. A glycolytic switch imposed by the absence of UCP2 could protect the neurons from ischemic damages.

CONCLUSION

  1. Top of page
  2. Abstract
  3. HISTORY OF THE FIRST UNCOUPLING PROTEIN, UCP1
  4. UCP2, A SINGULAR PROTEIN AMONG THE UNCOUPLING PROTEINS
  5. DO THE NEW UCPS EVEN HAVE UNCOUPLING ACTIVITY?
  6. UCP2 AS A METABOLIC SENSOR OR REGULATOR
  7. COULD PYRUVATE EXPORT EXPLAIN THE UCP2−/− MICE PHENOTYPES?
  8. CONCLUSION
  9. REFERENCES

The original studies with UCP1 were greatly facilitated by its abundance and its unequivocal role in nonshivering thermogenesis. Accumulating evidence suggest that although UCP2 is undoubtedly a member of the uncoupling family phylogenetically, its status as a functional uncoupling protein is less certain. For example, it remains questionable how UCP2 could catalyze a sufficiently high proton leak to allow for the degree of uncoupling needed for protection against oxidative stress taking into account its low intracellular abundance. The hypothesis that UCP2 exports pyruvate from mitochondria fits well with its tissue localization, its variation of expression depending on physiological situations as well as with the phenotypes observed in Ucp2−/− mice. With our model, uncoupling would be a side effect of the metabolic role of UCP2 rather than its primary function. While this model of Ucp2 as a “metabolic switch” is admittedly speculative, it should provide the theoretical framework for further experiments to define more fully the physiologic role of this interesting protein.

REFERENCES

  1. Top of page
  2. Abstract
  3. HISTORY OF THE FIRST UNCOUPLING PROTEIN, UCP1
  4. UCP2, A SINGULAR PROTEIN AMONG THE UNCOUPLING PROTEINS
  5. DO THE NEW UCPS EVEN HAVE UNCOUPLING ACTIVITY?
  6. UCP2 AS A METABOLIC SENSOR OR REGULATOR
  7. COULD PYRUVATE EXPORT EXPLAIN THE UCP2−/− MICE PHENOTYPES?
  8. CONCLUSION
  9. REFERENCES
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