Energy Metabolism of Neural Cells Under the Control of Phospholipases A2 and Docosahexaenoic Acid

C H A P T E R

9 Energy Metabolism of Neural Cells Under the Control of Phospholipases A2 and Docosahexaenoic Acid Peter Schönfeld⁎, Georg Reiser† ⁎

Institute for Biochemistry and Zell Biology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany †Institute for Inflammation and Neurodegeneration (Neurobiochemistry), Medical Faculty, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

ABBREVIATIONS ALA α-linolenic acid ANT ADP/ATP-antiporter CL cardiolipin DHA docosahexaenoic acid IMM inner mitochondrial membrane iPLA2 Ca2+-independent phospholipase LCFA long-chain fatty acids PPAR peroxisome-proliferator-activated receptor PTP permeability transition pore PUFA polyunsaturated fatty acids RC respiratory chain RET reversed electron transport ROS reactive oxygen species Δψ mitochondrial membrane potential

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ENERGY METABOLISM OF NEURAL CELLS AT A GLANCE Human brain tissue has a high energy demand, mostly needed for synaptic signaling. Consequently, according to a previously published detailed estimate,1 neurons contribute up to 85% (maybe even 95%) to the total energy required, although the cell number of astrocytes in brain tissue is much higher. ATP is generated in neurons predominantly by the oxidative phosphorylation machinery of mitochondria, whereas astrocytes provide the necessary ATP demand mainly by anaerobic glycolysis via substrate-level phosphorylation. Nevertheless, astrocytes are crucial for the fulfillment of the neuronal energy requirement (see for recent reviews Refs. 2–4). Chemical energy is predominantly supplied to the brain as glucose, taken up from the circulation by a concerted cooperation of the transporters Glut1 (from circulation) and Glut1 (from astrocytes) or Glut1 (from circulation) and Glut3 (from neurons). A growing number of reports have uncovered prominent differences in the use of glucose as fuel in astrocytes and neurons (see references in reviews2–4). Contrary to astrocytes, neurons do not store glucose as glycogen. Furthermore, even though astrocytes have high glycolytic capacity and are equipped with mitochondria, the end-product pyruvate becomes only poorly oxidized by the citric acid cycle for delivering reducing equivalents (NADH, FADH2) to mitochondria. This surprising finding is a result of maintaining the astrocytic pyruvate dehydrogenase in an inactive, phosphorylated state, achieved by the high enzymatic capacity of pyruvate dehydrogenase kinase 4 in astrocytes. Inactivation of the pyruvate dehydrogenase by phosphorylation enables astrocytes to generate lactate, and to donate it to neurons as fuel. Otherwise, neurons would be unable to respond to an enhanced energy requirement by upregulation of the glycolytic glucose degradation, because the enzyme 6-phosphofructo-2-/fructo-2,6-bisphosphatase, a positive key regulator of the glycolysis, is constantly degraded in proteasomes. In contrast, this enzyme is fully active in astrocytes, and, therefore allows the upregulation of glycolysis. In addition, methylglyoxal (reduced pyruvate) is formed as side-product during glycolytic glucose degradation.3 This highly reactive dicarbonyl compound methylglyoxal has been associated with the development of neurodegeneration. Contrary to neurons, astrocytes contain high capacities of glyoxalase enzymes for detoxification of methylglyoxal. This further enables astrocytes to deliver lactate to neurons. In conclusion, astrocytes generate through glucose degradation mostly lactate, whereas neurons use glucose preferentially for generation of NADPH by the pentose-phosphate pathway, and thereby protect their antioxidative status (e.g., by keeping glutathione in the reduced form). Furthermore, the energy requirement of neurons seems mostly based on the use of astrocytic lactate as energy-delivering substrate for the oxidative phosphorylation. According to the astrocyte-neuron lactate shuttle hypothesis, lactate as the final product of the astrocytic glycolysis is transferred to neurons by means of the monocarboxylate transporters MCT1/4 (astrocyte) and MCT2 (neuron).5,6 Neurons stimulate the astrocytic glycolysis through their synaptic activity via the combined release of glutamate from neurons and its subsequent uptake by astrocytes. Since glutamate uptake is coupled with co-uptake of Na+, the astrocytic Na+/K+-ATPase has the task to bring back Na+ from the cytosolic into the extracellular environment. Consequently, the ATP consumption by the Na+/K+-ATPase and, in addition, the ATP-dependent conversion of glutamate to glutamine, stimulates the

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glycolytic lactate generation by astrocytes. Two possibilities have been discussed for the fate of astrocytic lactate in neurons. Firstly, the cytosolic lactate dehydrogenase (LDH1) oxidizes lactate to pyruvate and NADH, and NADH is transferred into mitochondria by the malate– aspartate-shuttle (see for review Ref. 7). Alternatively, lactate is transported from the cytosol via a monocarboxylate transporter into mitochondria, where mitochondrial LDH oxidizes lactate to pyruvate plus NADH.4 Moreover, in sharp contrast to other organs with high-energy turnover, such as heart, kidney or liver, mitochondrial β-oxidation seems to play no role as hydrogen delivering process in brain. Nevertheless, the discussion on the capability of the brain tissue to degrade long-chain fatty acids (LCFAs) is still going on.8–10 Nevertheless, older (as we reviewed in Ref. 11) and more recent studies exclude mitochondrial β-oxidation in brain mitochondria and astrocytes.12,13 In addition, the high susceptibility of brain to reactive oxygen species (ROS)14 and the fact that β-oxidation would increase cellular oxidative stress, are further arguments against the use of fatty acid degradation for the hydrogen supply in brain tissue.15 However, brain tissue uses LCFA as energy source indirectly, namely in the form of liverderived ketone bodies (β-hydroxybutyrate and acetoacetate) during maturation in young age and upon prolonged fasting.16 Oxidation of liver-derived ketone bodies can replace glucose to a high degree because it provides up to 60% of the required energy.17 Being highly water soluble, the permeation of ketone bodies across the blood–brain barrier is mediated by the monocarboxylate transporters, MCT1–2.16 With respect to fatty acid oxidation, the use of ketone bodies as fuel is advantageous for the cerebral energy metabolism. This statement is substantiated by a lower oxygen consumption for oxidation of NADH derived from ketone body oxidation and, in addition, a lesser ROS generation due to the non-usage of the electron transfer flavoprotein-ubiquinone oxidoreductase in this pathway.18

DHA AND CA2+-INDEPENDENT PHOSPHOLIPASES A2 Docosahexaenoic acid (DHA; 22:6, n-3) is synthesized in the mammalian liver from αlinolenic acid (ALA; 18:3, n-3) by a series of desaturations, elongations, and one step of βoxidation.19 These reactions are located in the endoplasmic reticulum (desaturations, elongations) and in peroxisomes (β-oxidation). Hepatic conversion of ALA to DHA is considered to be sufficient for healthy individuals to meet the demand of DHA in the brain.19, 20 In addition, liver takes up dietary DHA and uses it for the production of phospholipids, which are released into the blood circulation. Brain has the ability to extract lipoprotein-bound DHA or its precursor ALA from the blood.19,21–23 Similarly to liver, brain has the enzymatic equipment to convert ALA into DHA. Moreover, DHA esterified to membrane glycerophospholipids is a further source for donating free DHA into the cerebral metabolism. In the glycerophospholipids, DHA is fixed to a high degree in the sn-2 position, from where it is liberated by the enzymatic activities of distinct phospholipases A2. Phospholipases A2 which are known for a long time to be enzymes were recognized already for two decades to have wide importance for many neurochemical processes.24 Briefly, phospholipases A2 form a superfamily, consisting of 16 groups (I–XVI).25 Group VI summarizes the so-called Ca2+-independent phospholipases A2 (iPLA2s), enzymes that exhibit some

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catalytic activity in the absence of Ca2+, and, in addition, have a serine residue in their catalytic center. It is believed that iPLA2 accounts for more than 70% of PLA2 activity in brain26 and, especially for the release of DHA.27,28 Two of them, the membrane-associated iPLA2β (PLA2G6) and iPLA2γ (PNPLA8) that are attached to mitochondria, have attracted particular attention. Moreover, in mammalian mitochondria iPLA2γ is the predominant phospholipase activity, and this phospholipase becomes markedly activated by divalent cations (Ca2+, Mg2+), by depolarization of the inner mitochondrial membrane (IMM) and by membrane-bound, negatively charged cardiolipin.29–31 Ca2+-induced iPLA2γ activation was completely inhibited by the CoA-derivates of LCFA.29 In addition, there is also a group of cytosolic PLA2 (cPLA2) in brain.32 cPLA2 is activated after translocating to the plasma membrane from the cytosol, where it remains then constitutively membrane bound. In contrast to iPLA2, cPLA2 preferentially catalyzes the release of arachidonic acid28 and, is thereby involved in the production of arachidonic acid-derived lipid mediators, such as prostaglandins, thromboxanes, and leukotrienes, for brain metabolism.32

MULTIPLE CELLULAR PROCESSES UNDER THE CONTROL OF DHA As a lipid molecule consisting of 22 carbon atoms with 6 double bonds, DHA can exists in multiple configurations, and so it can change after its incorporation into cellular membranes, the membrane properties. With respect to other LCFA, the DHA molecule has a greater molecular volume (355 Å3). This feature results in increased membrane fluidity, when DHA becomes esterified with membrane phospholipids.33 As a consequence, various membrane-associated functions such as transmembranal drug permeability, carrier-mediated metabolite transport, activities of membrane-bound enzymes, ion channels and receptors, and neurotransmission are modulated by the increased membrane fluidity.33–37 Brain has a particularly high demand for DHA during pre- and peri-natal development. In this period, synaptogenesis, dendrite formation, and other neural membrane building processes take place, to form brain circuit structures.20 Moreover, similar to other members of the PUFA family, DHA can be active in diverse intracellular functions, such as being an effector of intracellular signaling, of immune response, and in homeostasis of the metabolism in tissues.38 In more detail, DHA and other PUFAs are metabolized to resolvins (dihydroxy or trihydroxy metabolites of DHA), which have anti-inflammatory activity.39 Furthermore, DHA operates as endogenous ligand of PPAR-γ and PPAR-α. Thus activation of PPAR-γ by DHA is involved in the microglial activation, myelination, and heat shock protein response.38 Finally, DHA displays also anti-inflammatory properties by activation of cPLA2. The underlying mechanism is mediated by the GPR120 receptor, and results in the production of prostaglandin A2.40 DHA operates either directly as signaling molecule or serves as precursor of docosanoids, which are sustaining neural cell integrity.20,32,33,41 It has been also proposed that a DHArelated intracellular Ca2+-mediated signaling contributes to a regulation of a brain-specific prostaglandin formation.42 Importantly, despite their function in brain tissue, DHA and other PUFA have the potential to counteract insulin resistance, probably by modulating mitochondrial bioenergetics.43

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Ambiguous Role of DHA in Oxidative Stress Events

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AMBIGUOUS ROLE OF DHA IN OXIDATIVE STRESS EVENTS Basically, high cerebral capacity of oxygen-dependent energy turnover combined with low intrinsic capacity of antioxidant defense and high content of polyunsaturated lipids requires an effective protection of the nonregenerating neurons against the harmful action of ROS. For that purpose, neurons receive strong antioxidative support, particularly from astrocytes, which supply neurons with precursors for the synthesis of glutathione, to allow the inactivation of ROS.44 Generally, depending on the metabolic condition, LCFAs can either increase or decrease the intracellular ROS generation. There are three mechanisms accounting for the possibility that DHA modulates mitochondrial ROS generation (see Fig. 1 for mitochondrial targets of DHA, which contribute to ROS generation): Firstly, as a potential substrate of the mitochondrial and peroxisomal β-oxidation in noncerebral tissues, DHA is able to donate electrons to the ROS generation.45–48 Secondly, nonesterified DHA or their activated acyl-CoA derivative are able to impair the electron flux within the respiratory chain (RC), and thereby enhance ROS generation (for review, see Refs. 18, 49, 50). This has been shown with rat brain mitochondria51 and rat pheochromocytoma cells (PC12), a model of neural cells.52 Since PC12-associated ROS generation was paralleled by an increase of glycolytically generated lactate and, in addition, negatively correlated with the mitochondrial NADH-cytochrome c reductase activity, it is highly suggestive to attribute the ROS generation to an impairment of the electron transport in the RC by DHA. Thirdly, slight depolarization of the IMM by “mild-uncoupling” by nonesterified DHA dramatically decreased a ROS generation, which was driven by reversed electron transport (RET).51 This strong dependency of RET-dependent ROS generation on the mitochondrial membrane potential (Δψ) has attracted attention to iPLA2 as a tool to liberate DHA from membrane lipids.53 Additional evidence showed that the uncoupling protein-2 reduces in concert with an H2O2-activated mitochondrial iPLA2 oxidative stress in the cell. According to this view, fatty acids released from membrane phospholipids initiate uncoupling protein2-mediated “mild-uncoupling.” It is also worth to mention that a diminished activity of iPLA2γ correlates reciprocally with increased mitochondrial peroxidation and mitochondrial dysfunction in a rotenone-induced model of Parkinson’s disease.54 This finding suggests that iPLA2γ acts in the midbrain as a protective enzyme throughout oxidative stress. Moreover, being a polyunsaturated fatty acid, DHA is highly susceptible to peroxidative damage. Therefore, it was surprising that, despite of its abundance in brain tissue, DHA decreased lipid peroxidation (see for review Ref. 33). This discrepancy is explained by the ability of DHA to increase the capacity of antioxidative enzymes, such as catalase, glutathione peroxidase, and glutathione reductase. DHA-associated neuroprotection has been demonstrated with studies, where DHA was esterified in membrane phospholipids.55 A further likely mechanism for the neuroprotection by DHA is the stimulation of plasmalogen synthesis, driven by the DHA-regulated expression of enzymes involved in their synthesis.56,57 Remarkably, in plasmalogens, the double bond of the vinyl-ether bound sidechain at the sn-1 position is highly reactive to ROS, thereby transforming plasmalogens into natural scavengers for ROS. In addition, a derivative of DHA, called neuroprotectin D1 (10,17S-docosatriene), exhibits neuroprotection after episodes of ischemia–reperfusion. This activity of neuroprotectin D1 is ascribed to the upregulation of the antiapoptotic proteins Bcl-2 and BclxL and the decrease of the proapoptotic proteins Bax and Bad.

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FIG. 1  Modulation of mitochondrial energy-related activities connected with the inner mitochondrial membrane (IMM) by docosahexaenoic acid (DHA) and iPLA2. Binding of nonesterified DHA to the mitochondrial permeability transition pore (PTP) facilitates its opening and, consequently, DHA reduces cell viability. Moreover, elevated concentrations of DHA exert a dual action on ROS generation by the respiratory chain (RC). Interaction of DHA with components of the RC slows down the forward electron transport, thereby stimulating the generation of superoxide (O2−.). Otherwise, the uncoupling activity of nonesterified DHA, being a characteristic feature of long-chain fatty acids, diminishes the mitochondrial membrane potential (Δψ) across the IMM by enhancing the back-transport of H+ from the cytosolic compartment (H+ leak). Modulation of H+ leak has been also attributed to iPLA2. In conclusion, due to the decline of Δψ, the O2−. generation driven by reverse electron transport becomes abolished. In addition, DHA partly inhibits phosphorylation of ADP to ATP by interaction with constituents of the F0F1-ATPase and, has the capacity to partly reduce the export of matrix-formed ATP to the cytosol via the ADP/ATP-antiporter (ANT). Besides these activities of DHA on the IMM and their protein components, DHA serves as precursor for the formation of second messenger lipids (docosanoids). Finally, iPLA2 itself is able by its enzymatic activity to remove peroxidatively damaged fatty acid chains from cardiolipin (CL) and thereby, helps to regenerate CL. This feature of iPLA2 is essential for sustaining energy-driven mitochondrial functions in cells.

Finally, cardiolipin is nearly exclusively present in the IMM, and it is located in the proximity of ROS-generating sites. For that, and due to multiple bis-allylic hydrogen atoms (-HC=CH-CH2-HC=CH-) in cardiolipin, this phospholipid is highly susceptible to oxidative stress. There is evidence that iPLA2γ released peroxidized fatty acid chains from cardiolipin, and thereby, pathological products which are able to disturb energy conversion by mitochondria.31

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Alteration of Mitochondrial Energy-Dependent Functions

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ALTERATION OF MITOCHONDRIAL ENERGY-DEPENDENT FUNCTIONS A growing number of reports revealed an important role of iPLA2γ in animal energy metabolism, particularly for maintaining bioenergetic functions of mitochondria. An early study reported that mitochondria isolated from the heart of iPLA2γ−/− mice exhibits a 65% decrease in the ascorbate-mediated activity of Complex IV.58 More importantly, skeletal muscle mitochondria59 and liver mitochondria60 from iPLA2γ-ablated mice have a dramatically decreased ADP-stimulated respiration. This decrease was independent of the type of substrates (pyruvate plus malate or succinate or pyruvate plus glutamate) used for donation of reducing equivalents (NADH or FADH2) to the RC. Moreover, the reduced capacity of oxidative phosphorylation results probably from a slight uncoupling of the ATP-synthase reaction and the electron transport within the RC. Since in mitochondria from iPLA2γ−/− mice the cardiolipin content is also lower, it has been speculated that the uncoupling results from a greater H+ leakage of the IMM. Taken together, iPLA2γ is an obligatory upstream enzyme essential for oxidative ATP production. In line with this conclusion are the findings that iPLA2γ−/− mice suffer from growth retardation, cold intolerance, reduced exercise endurance, and are resistant to high fat diet-induced weight gain.58,59 Notably, ablation of iPLA2γ is also causal for mitochondrial degeneration in brain, as indicated by an alteration of their lipid metabolism and membrane structure.61 These findings are accompanied by cognitive dysfunctions. Similar to iPLA2γ, iPLA2β also contributes to the maintenance of mitochondrial respiration and ATP synthesis.62 In addition, with brain mitochondria isolated from mice it was demonstrated that a defective activity of iPLA2β decreased the ability of mitochondria to take up and retain Ca2+.63 Since Ca2+ is known to be a universal second messenger (for review see Ref. 64), this finding suggests a function of mitochondria-bound iPLA2 as regulator of cytosolic Ca2+ concentration. This view is supported by their ability to sense micropools of high Ca2+ concentrations created by the InsP3-mediated opening of the Ca2+ store near of the endoplasmic reticulum.65 In addition, by means of the reversible Ca2+ uptake and release, mitochondria control the activity of pyruvate dehydrogenase and two dehydrogenases of the citric acid cycle (tricarboxylic cycle).66 Moreover, there are arguments suggesting that iPLA2γ plays a role in the opening of the mitochondrial permeability transition pore (PTP) and, thereby acts as a trigger initiating apoptotic cell death (see Fig.  1). Firstly, it has been reported that activated iPLA2γ is involved in the release of apoptogenic factors, such as cytochrome c, Bax, or Bid.67,68 Secondly, an involvement of the iPLA2γ in the intrinsic apoptotic cell death is substantiated by their capacity to release nonesterified LCFAs or their acyl-CoA derivatives, to trigger the Ca2+-induced opening of PTP.60 Thirdly, genetic ablation of mt-iPLA2γ attenuates Ca2+induced opening of PTP in liver mitochondria and thus, the release of the apoptogenic cytochrome c.60 Since liver mitochondria from iPLA2γ−/− mice were much more resistant to Ca2+-induced swelling in the presence or absence of phosphate in comparison with wildtype littermates, iPLA2γ is considered to be a critical mechanistic participant in the Ca2+induced opening of PTP. It is highly suggestive that some of the iPLA2γ-associated changes in the mitochondrial functions are directly mediated by nonesterified DHA. Fig. 1 shows some of the main targets

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of DHA. Isolated mitochondria exposed to low micromolar concentrations of DHA exhibit slight depolarization of the IMM, a partly impaired ADP/ATP-antiporter and a slightly impaired electron transport within the RC.51,52 In addition, DHA most likely inhibits the phosphorylation of ADP to ATP by an interaction with constituents of the F0F1-ATPase (see Fig. 1). In summary, these activities can explain a lowered efficacy for oxidative ATP regeneration in the presence of micromolar concentrations of DHA. Moreover, as also indicated in Fig. 1, notably, the activation of iPLA2γ by cardiolipin (CL) has consequences for the mitochondrial bioenergetics during oxidative stress and intracellular signaling.31 Firstly, CL-activated iPLA2γ mediates the hydrolysis of arachidonic acid from phosphatidylcholine, thereby integrating the production of lipid messengers from different lipid classes in mitochondria. Secondly, CL-activated iPLA2γ removes peroxidized fatty acids from CL, thereby offering the way for the reesterification of CL with intact fatty acids. Finally, it is also worth to recall that CL itself exerts an important role in the mitochondrial bioenergetics and mitochondria-associated signaling.69–71 In spite of many other proteins of IMM, CL is required for the optimal activity of the complexes I, III, and IV of the RC as well as complex V (ATPase). One example for the bioenergetic consequences of CL-deficiency is clearly illustrated by the pathomechanisms found in Barth syndrome.72 There, the underlying changes in composition of CL-aliphatic chains due to a defective CL remodeling result in mitochondria with decreased quality control.

CONCLUSIONS Brain differs greatly from other tissues with respect to its distinct energy metabolism and susceptibility to oxidative stress. For maintaining the supply of energy, brain uses mostly the energy of glucose, whereas that of hydrogen-rich fatty acids, including DHA, is spurned. Nevertheless, besides a multiplicity of physiological functions in tissues, DHA protects and modulates the energy metabolism of neural cells. One strategy is “mild-uncoupling,” thereby attenuating attacks of ROS on the system of a myriad of proteins, enzymes, unsaturated sidechains of membrane lipids and metabolite carriers involved in oxidative ATP generation and, the integrity of cerebral membranes. DHA-associated protection against oxidative stress is additionally supported by two further features of the molecule DHA. Firstly, DHA is a main constituent of cerebral membrane phospholipids and, secondly, it acts due to its highly unsaturated nature as an antioxidant. iPLA2s account for more than 70% of the total phospholipase A2 activity. Besides others, their physiological role comprises the release of DHA for the synthesis of second messenger lipids and the membrane remodeling. The latter contributes to the removal of peroxidatively damaged fatty acid chains, and, thus, allows their subsequent substitution by nondefective fatty acid chains in CL. Moreover, studies mimicking deficiency of the iPLA2 have uncovered the role of DHA in sustaining effective oxidative phosphorylation (iPLA2γ) and in the intracellular Ca2+ homeostasis (iPLA2β). Lack of activity of iPLA2β in mitochondria decreased their ability to take up and retain Ca2+. In addition to the iPLA2related functions, DHA directly modulates several activities of protein complexes of IMM and, thereby, affects the cellular energy metabolism. In conclusion, by targeting mitochondria, DHA severely affects the cellular energy metabolism.

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REFERENCES 139

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B.  OMEGA FATTY ACIDS: BRAIN AND NEUROLOGICAL DEVELOPMENT