Fatty acids in energy metabolism of the central nervous system - PubMed (original) (raw)
Review
Fatty acids in energy metabolism of the central nervous system
Alexander Panov et al. Biomed Res Int. 2014.
Abstract
In this review, we analyze the current hypotheses regarding energy metabolism in the neurons and astroglia. Recently, it was shown that up to 20% of the total brain's energy is provided by mitochondrial oxidation of fatty acids. However, the existing hypotheses consider glucose, or its derivative lactate, as the only main energy substrate for the brain. Astroglia metabolically supports the neurons by providing lactate as a substrate for neuronal mitochondria. In addition, a significant amount of neuromediators, glutamate and GABA, is transported into neurons and also serves as substrates for mitochondria. Thus, neuronal mitochondria may simultaneously oxidize several substrates. Astrocytes have to replenish the pool of neuromediators by synthesis de novo, which requires large amounts of energy. In this review, we made an attempt to reconcile β-oxidation of fatty acids by astrocytic mitochondria with the existing hypothesis on regulation of aerobic glycolysis. We suggest that, under condition of neuronal excitation, both metabolic pathways may exist simultaneously. We provide experimental evidence that isolated neuronal mitochondria may oxidize palmitoyl carnitine in the presence of other mitochondrial substrates. We also suggest that variations in the brain mitochondrial metabolic phenotype may be associated with different mtDNA haplogroups.
Figures
Figure 1
Motoneuronal perikaryon and its synaptic covering Motoneuronal perikaryon and its synaptic covering. Parent fibers are not shown. Dendrites are covered with boutons at all distances from cell body. Notice astrocytic processes cover some of oligodendrocytic surface as well as motoneuronal. (Adapted from Poritsky [72]).
Figure 2
Photomicrograph of a cerebellar Golgi cell. The cell was juxtacellularly filled with neurobiotin and viewed in dark field at magnification of 240x. The soma, principal dendrites, and a diffuse cloud of axon terminals are visible, each terminal corresponding to a contact with one of thousands of granule cells (adapted from Holtzman et al. [73]).
Figure 3
Mitochondrial pyridine nucleotides in freshly isolated rat liver and brain mitochondria incubated in the absence of added substrates. Incubation medium contained 120 mM KCl, 10 mM NaCl, 2 mM MgCl2, 2 mM KH2PO4, 20 mM MOPS, pH 7.2, 1 mM EGTA, and 0.7 mM CaCl2. Mitochondrial protein 0.5 mg/mL. Fluorescence of mitochondrial NAD(P)H was measured as described in [74].
Figure 4
Schematic representation of the mechanism for glutamate-induced glycolysis in astrocytes during physiological activation (from [93]). At glutamatergic synapses, presynaptically released glutamate depolarizes postsynaptic neurons by acting at specific receptor subtypes. The action of glutamate is terminated by an efficient glutamate uptake system located primarily in astrocytes. Glutamate is cotransported with Na+, resulting in an increase in the astrocytic sodium concentration leading to activation of the astrocyte Na+/K+-ATPase. Activation of the Na+/K+-ATPase stimulates glycolysis, that is, glucose consumption and lactate production. Lactate, once released by astrocytes, can be taken up by neurons and serves them as an adequate energy substrate. (Note: from further reading of the paper, it becomes clear that “PGK” should, in fact, be “PDH,” pyruvate dehydrogenase, which provides acetyl-CoA to the TCA cycle and further electrons to respiratory chain of mitochondria.)
Figure 5
Simultaneous operation of aerobic glycolysis and the fatty acids supported tricarboxylic acid cycle and oxidative phosphorylation in the astrocyte. Enzymes: LDH: lactate dehydrogenase, APC: ATP-dependent pyruvate carboxylase, 1–9: the enzymes of the TCA cycle, which operates clockwise, GLDH: glutamate dehydrogenase, and GS: glutamine synthetase.
Figure 6
The malate-aspartate shuttle (MAS). The mitochondrial inner membrane is impermeable for NADH. In order to effectively utilize lactate for mitochondrial respiration, lactate must be converted to pyruvate in the reaction lactate + NAD+→ pyruvate + NADH. NADH is reoxidized by the MAS. The process is unidirectional because GAT (aralar) is electrogenic and the matrix NADH is rapidly oxidized by the respiratory chain.
Figure 7
Respiratory activity and membrane potential of the rat (Lewis) brain mitochondria isolated in the absence (a) and in the presence (b) of 0.1% BSA. Incubation conditions: 125 mM KCl, 10 mM NaCl, 10 mM MOPS, pH 7.2, 2 mM MgCl2, 2 mM KH2PO4, 1mM EGTA, and 0.7 mM CaCl2. At Ca2+/EGTA = 0.7, the [Ca2+]Free was 1 µM. Chamber volume = 0.65 mL. Substrate: succinate 5 mM, no rotenone was added. Additions: BM 0.3 mg, ADP 150 _μ_M, and CCCP 0.5 _μ_M. Numbers at the traces are respiratory activities in nmol/min/mg mitochondrial protein. Respiratory activity ratio (RCR) is V State 3/V State 4.
Figure 8
Respiratory activity and membrane potential of the rat (Sprague Dawley) brain mitochondria isolated in the absence of 0.1% BSA. Incubation conditions as in Figure 7. Substrates: pyruvate 2.5 mM, malate 2 mM. Additions: ADP 150 _μ_M and CCCP 0.5 _μ_M. Numbers at the traces are respiratory activities in nmol/min/mg mitochondrial protein.
Figure 9
Generation of H2O2 by non-BSA rat brain mitochondria oxidizing various substrates and substrate mixtures. Incubation conditions as in Figure 7. Substrates: pyruvate 2.5 mM, glutamate 5 mM, succinate 5 mM, and malate 2 mM. The method of ROS measurements was described in [10]. Statistics: ***P < 0.001; NS: not significant.
Figure 10
A schematic presentation of operation of the tricarboxylic acid cycle in brain mitochondria oxidizing glutamate and pyruvate. The figure was adapted from [95]. Abbreviations: AST: aspartate aminotransferase, ALT: alanine aminotransferase, and SDH: succinate dehydrogenase. The symbol of the closed lock means the step catalyzed by SDH is inhibited. The dashed arrows indicate inhibitory influences of malate and oxaloacetate on SDH.
Figure 11
Oxygen consumption by rat (Sprague Dawley, 2010) brain mitochondria isolated without BSA oxidizing various substrates and their mixtures in different metabolic states. Experimental conditions as described in Figure 6. Metabolic states are shown in Figure 7. Substrates: glutamate 5 mM, malate 2 mM, pyruvate 2.5 mM, succinate 5 mM, and palmitoyl carnitine 25 _μ_M. Numbers at the traces are respiratory activities in nmol/min/mg mitochondrial protein. Respiratory activity ratio (RCR) is V State 3/preceeding V State 4. Additions: brain mitochondria 0.3 mg, ADP 150 _μ_M, CCCP 0.5 _μ_M, and glutamate 5 mM.
Figure 12
Respiratory activity and ROS production by rat brain mitochondria oxidizing palmitoyl carnitine in various substrate mixtures. Incubation conditions as in Figure 7 and substrate mixtures as described in Figure 11. The data are average of three different isolations (M ± standard error). ROS production was measured with the Amplex red method as described in [10]. The minimal rate of ROS production was observed with glutamate + malate, which was taken as 100%.
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