Index

Acetate Alkyl DHAP synthase, 414 – quantitative autoradiography, – in the study of pyruvate Alpha-ketoglutarate/glutamate 403, 404 recycling, 189 exchange, 64, 75 – subfractionation, 403, 404 Acetoacetate, 139, 147, 154, 163, See also Alzheimer’s disease (AD), See Analytical (issues), 893, 896, 901, 907 Ketone bodies Neurodegenerative diseases Anaplerosis, 183–192, 203, 208, 209, Acetoacetyl coenzyme A Amino acids 213, 222 (acetoacetyl-CoA), 163 – GABA, 571, 574, 575–578 – definition of, 184 Acetoacetyl-CoA thiolase, 163, 166 – glutamate, 571, 573–581 – function of, 184–186 Acetyl coenzyme A (acetyl-CoA), – , 571, 573–580 Anaerobic , 772

142, 163 Ammonia, 204, 215, 222, 223, 225, Anesthesia (effect on CO2 fixation), 190 Acetylcholine, 298, 300–302, 304, 227, 228 Angiogenesis, 120 306–308 g-Amino butyric acid, See GABA Anoxia, 20, 23, 25 Acid/base g-Aminobutyric acid (GABA) – effects on synaptic transmission, – coupled transport, 476, 480 receptor, 248 26–28 – flux, 470, 471, 474 g-Aminobutyric acid, 590, 591, 603 Antioxidant, 307, 312, 313, 706, 709, – homeostasis, 480 6-Aminonicotinamide, 45 710, 712, 721, 723 – regulation, 470, 474, 476, 480 Aminophospholipids, 406, 409–411, – mitochondrially targeted, – transients, 471 417, 420 525, 534 – transporters, 473–477 5’-AMP-activated protein kinase APO-E, 898 Acid-sensing ion channel (ASICs), 476 (AMPK) Apoptosis, 531, 534, 536, 538, 668, 669, Activation, See Brain – activation of glucose uptake 673, 681, 684, 687 Acyl-CoA by, 496, 503, 504 – caspases in, 714, 715, 721 – dilution factor l, 419 – activation of glycolysis by, 506, 507 – death receptor pathway of, – precursor pool, See – and activation of 715–717 Compartmental model, brain 6-phosphofructo‐2-kinase – in brain development, 715 Acyl-CoA synthetase, 407, 409, 417, 419 (PFK2), 508 – in neurodegenerative diseases, 713 Adenine Nucleotide Transporter – nitric oxide-mediated activation – intrinsic mitochondrial pathway (ANT), 879, 882 of, 492, 493 of, 715, 716 Adenine nucleotides, 645 AMP-activated protein kinase (AMPK), – regulation by Bcl‐2 family Adenosine, 253 642, 651, 654 proteins, 716–720 phosphotransfers, Amyloid, 890, 898 – role of in, 705, 649, 652 Amyotrophic Lateral Sclerosis (ALS), 707–709 Aerobic glycolysis, 772, 782 538, 890, 902, 905, 906 Apoptosis inducing factor (AIF), 532, Aging, 298–302, 305–310, 314, 782 Anaerobic glucose , 28 536, 715 – antioxidants, 284, 285, 288 Analysis, 890, 892, 901, 903, 904 Arachidonic acid – free radicals, 284 Analytic procedures, brain lipids – cascade, 407, 419 – oxidative damage, 270, 281, 283 – for acyl-CoA, 407 – concentration, brain, 409 Aglycemia, 20 – gas chromatography and mass – conversion to arachidonoyl-CoA, AK1b isoform, 649 spectroscopy(not found) 407 Alanine, 140, 204, 210, 223–230 – high energy microwaving, – conversion to eicosanoids by Alcoholism, 54 importance, 404 COX‐1 and COX‐2, 407 Aldolase (ALD), 242, 773 – positional selectivity – half-life, in brain Aldose reductase, 53 fatty acids, 406 phospholipids, 408

# Springer-Verlag Berlin Heidelberg 2007 914 Index

– in ischemia, release and – for maintaining Batten disease, 899 recycling, 405 aminophospholipid Bax – inhibition by NSAIDs, 419 asymmetries, 420 – activation of, 717, 720

– release by phospholipase A2, – phosphatidylinositol, – inhibitors, 722 418, 419 411, 413 Bcl family proteins, 525 – toxicity at high concentrations, – by phosphatidylinositol cycle, Bcl‐2 family proteins 417 402, 411, 412, 413 – anti-apoptotic, 717, 720, 722, 723 – turnover (recycling), in brain – by phospholipid metabolism, – BH3-only subgroup of, 719 phospholipids, 407 402, 405, 407, 418 – classification of, 718 ARD1, 777, 778 – homeostasis during activation, – in neurodegenerative diseases, 718 ARNT2, 775 370–371 – mitochondrial mechanisms of ARNT3, 775 – hydrolysis, 122–124, 126–127 action, 716 Artificial cerebrospinal fluid (ACSF), 244 – rotation, 120, 122–124 – pro-apoptotic, 717, 720 Arylhydrocarbon receptor nuclear – central rotor, 125 – role in mitochondrial apoptotic translocator (ARNT), 775 – central stalk, 124–126 pathway, 715, 716, 721 Asparaginyl hydroxylase, 777 – cross-linking, 122–124, 128 Beckman LS 6500 scintillation Aspartate, 590, 591, 598, 599, 601, 602, – lateral stalk, 125, 126, 128 spectrophotometer, 244 605–610 – nucleotide binding, 123, 124 BH3-only proteins, 705, 717, 719, 720, Assembly factors, 128 – optical microscopy, 123 721 Assembly of respiratory complexes – PARAP, 123 bHLH-PAS transcription factor, 775 – factors of, 109 – peripheral stalk, 121 Bicarbonate – intermediates of, 103, 104, 108 – rotary motor, 121, 125 – in propionyl‐CoA – pathway of, 108 – rotor element, 126 carboxylation, 190 Astrocytes, 64–67, 71, 74, 75, 79, 80, 83, – single molecule experiments, – in pyruvate carboxylation, 85, 86, 184–192, 199–204, 206–230, 124, 126 189, 190 502–504, 531, 688, 689, 774, 778, – stator, 121, 125–127 Biliverdin reductase, 53 780, 881, 882, 884 – stator, 121, 125–127 Biochemical Systems Theory (BST), – biosynthesis of nitric oxide by, – subunit c rotation, 126 868, 869, 871 488–490 – substeps, 123 Biogenesis, 128, 129 – and lactate dehydrogenase – subunit c rotation, 126 Biomarkers, 899, 905, 906 (LDH), 143, 148, 149, 152, 153 – synthesis, 120, 123, 124, 127 Biotin, 186, 187, 191, 192 – functional properties, 363 – aminophospholipid – deficiency of, 192 – glycolytic capacity, 365, 368, asymmetries, 417 – in biotin-dependent 369, 389 – cell death, 407 carboxylases, 192 – metabolic properties, 363, 368 – debt, 407, 418, 419 – metabolizing and their – monocarboxylate transporters in, – depletion, effect on, 417 deficiency, 192 144, 164, 169 – excitotoxicity, 417 Blood flow – oxidative capacity, 363, 365, 366, – fatty acids, 417 – regulation of 368, 388, 392 – glutamate release, 417 – nitric oxide, 380, 382, 383 Astrocyte-Neuron Lactate Shuttle – production rate, 406 – potassium, 382, 383 Hypothesis (ANLSH hypothesis), – by brain, 403, 406 – prostanoids, 380, 383 148–154, 168, 881, 884 – coupled to, 406 Blood-brain barrier (BBB) Astrocytic-neuronal trafficking in – glucose and oxygen – expression of MCT1 in, during cataplerosis, 189 consumption, 405, 406 development, 145, 166 ATP, 5–11, 13, 14, 185–187, 189, 191, – human brain, 405, 406 Blood-brain barrier, 187, 189, 404 430–442, 444–452, 454, 457, 520, – oxidation, 406 BOLD Signal, 378–380 531, 535, 537, 538, 550, 557–562 – P/O ratio, 405, 406 Bongkrekic acid, 9 – consumption, 403, 405–420 – phosphatidylinositol, Brain – by brain, 403, 406, 419, 420 411, 413 – activation –byde novo synthesis, 416, 420 – rat brain, 406 – ATP homeostasis during, – ether phospholipids, 406, 407, ATP , 120 384–388 414–416, 420 ATP synthase, 706, 708, 714, 879, 881 – BOLD signal changes during, – by fatty acid turnover in ATP/ADP carrier = Adenine Nucleotide 378–380 phospholipids, 407 Transporter (not found) – cellular activity during, 388

– increased, during recovery ATP-sensitive potassium (KATP) – definition of, 349, 350 from ischemia, 418 channel, 642 – energy metabolism during, –byNa+/K+-ATPase pump, 402 Autoradiography, 64, 73, 74, 79 371–377 Index 915

– global steady-state changes Ca2+, 529–533, 537 Cerebral cortex slices, energy during, 371, 372 Calcium, 298, 300, 306, 307, 309, 310, metabolism of, 21 – glycolysis during, 384–386 312–315, 436–443, 445, 447, Cerebral ischemia, 779, 780 – hydrolysis of phosphocreatine 452–455, 668, 669, 671–677, 680, Chemosensitive neurons, 475, 476 during, 384 681, 684–689, 708, 712, 719, 721 Chloramphenicol, 880 – ion homeostasis during, Caloric or dietary restriction (CR), 899 Chloride-bicarbonate exchanger (AE), 370, 371 cAMP-response element binding 474 – localized changes in response protein (CREB), 657 Cholesterol, 314 to stimulation, 372, 373 Cancer, 535, 782, 783 4-CIN, 159 – metabolic compartmentation Carbonic anhydrase, 470, 475, 479 Citrate, 139, 162, 164 during, 388–391 Cardiac energy metabolism Classification, 891, 894, 896, 898, 899, – metabolite changes during – basic laws of cardiac physiology 902, 906 tissue, 373–377, 389 and energetics, 818, 819 Clinical (practice), 904–906 – metabolite changes during – regulation of mitochondrial c-Myc, 783

vascular, 373–377 respiration in vivo, 819, 820 CO2 fixation, 186, 188–190 – oxidative phosphorylation – the phenomenon of functional – magnitude in brain, 189

during, 386–388 coupling in the CO2 sensitivity, 476 – reaction potential changes system Cobalt chloride CoCl2, 777, 780, 782 during, 386 – membrane-bound creatine Cognitive impairment, 645 – stages of, 350, 351 kinases, 822 COMET, 898, 905 – energy metabolism, 348–351 – mitochondrial creatine Compartmental Model, brain – work, 345–347 kinase, 820, 821 – arterial input function (integrated – substrate delivery during, – myofibrillar creatine plasma specific activity), 404 377–382 kinase, 822 – ATP stoichiometry, 405 – activity levels Caspase – beta-oxidation, 404 Brain,SeeCompartmental Model – in brain development, 715 – dilution factor l, 404 Brain aging, 166 – inhibitors, 721 – equations for, 404, 405 Brain development – initiator and effector, 715, – figure of, 404 – and activities, 165, 166 717, 721 – fluxes, 404 Brain energy metabolism Catalysis – half-life, 405 – adult brain, 847, 848 – binding change mechanism, – incorporation coefficient, 405 – creatine kinase system and ATP 122, 123 – precursor pool, 404, 405 metabolism, 847–849 – bi-site, 122–124 – programmed intravenous – the developing brain, 848, 849 – catalytic sites, 122–124 infusion, 403 Brain homogenates, 164–166 – cooperative interconversion, 122 – specific activity, 404 Brain mitochondria – kinetic data, 122 – stable lipid compartments, 404 – astrocytic, 287 – tri-site, 122, 124 – steady-state assumption, 404 – axonal, 279, 280 – uni-site, 122 – turnover rate, 403–405 – dendritic, 280, 285 Cataplerosis, 185, 189 Compartmentalized energy transfer, – glial, 270, 272 – definition of, 184 817, 818, 820, 834, 845, 846, 848 – neuronal, 270, 281, 283 – function of, 186 – description of the model, – oligodendrocytic, 287 Cell death, 668, 671, 673, 674, 681, 838, 839 – somatic, 280 684–689 – non-equilibrium state of the – synaptic, 280 – apoptotic, 704, 717, 719, 720, 721 creatine kinase system, 839–842 Brain slices, 145, 146, 156, 158, 160, 162, – caspase-independent,721 – the modeling of 165, See also Hippocampal slices – necrotic, 704, 705, 719, 720 compartmentalized energy – energy utilization in, 21–23 – role of MPT in, 709 transfer in the cells, 837–842 – inhibition of energy metabolism Cellular activity, 388–391 Compartmentation, 201, 208, 228–230 in, 23 Cellular bioenergetics – enzyme complement, 280 – positive and negative features of, infrastructure, 644 – metabolism, 275, 280, 281 18, 19 Central dogma, 890 – TCA cycle, 275 Brain, 79–81, 86, 668, 669, 671–674, Central Nervous System (CNS) Complex I, 520 677–679, 680–682, 684, 685, – programmed cell death in, 704 Complex I, 879, 881 687, 689 Cerebellar granule cells, 190 Complex III, 520, 526, 527, 530, 531, Brown adipose tissue (BAT), 550–556, – pyruvate carboxylation in, 190 534, 538, 539 558–561, 563 Cerebral activation, 65, 75, 79, 81, 82, Complex IV, 878, 879, 881 Buffer capacity, 472, 473, 477, 481 85, 86 Complex V, 120, 128, 129 916 Index

Compound action potential (CAP) Deoxynucleotide diphosphates – effects of oxygen and glucose – and fructose, 160 (dNDPs), 650 deprivation, 25 – and glutamine, 161, 162 Deoxyribonucleotides, 645 – effects of temperature, 22 – and lactate, 145, 156, 159 Design (experimental), 893, 895, 903, 907 – energy use rates, 23 – and mannose, 160 Development – coupling with neural activity, – and b-hydroxybutyrate, 165 – apoptosis, 286 323, 330 Connectivity theorem, 871, 880 – proliferation, 286 – mitochondria, 324, 325 Control coefficient, 868–872, 878–881, DFO, 777, 780, 782 – monitoring by fluorescence 883, 884 Diabetes, 53, 54, 155 measurement, 326 Conventional hypothesis of glucose Dichlorofluorescein (DCF), 524, 526 – oxygen metabolism, 324, 325 utilization, 148, 149 Diffusional nucleotide exchange Enolase (ENO), 773, 779 Coordinate response, 772 – facilitated, 645, 646 Environment, 891, 893, 895, 898, 902, Creatine kinase, 643 – reaction based, 646, 647 904, 907 Creatine, 5, 883 – simple, 645 Epidermal growth factor (EGF), 780 Creatinephosphate, 5 Dihydroethidium(DHE), 524 Epilepsy, 192 Culture Dilution factor l, 404, 408, 413, 419 EPO, 776–780 – astrocyte-neuronal interactions, – equation for, 404, 405 Excitatory postsynaptic potential 570, 573 – in ischemia, 405 (EPSP), 24 – astrocytes, 575, 577 Disc herniation, 904, 905 Excitotoxicity, 451, 452, 453, 456, 557, – cerebellar cultures, 574 Dopamine, 298, 300, 301, 304–306, 562, 708, 709, 718, 720, 721

– co-cultures, 574 308–310, 312–314 F0F1-ATPase, 557 – cortical cultures, 577 Dopaminergic, 300, 305 F1 – neurons, 570, 574 DRAL/FHL‐2 protein, 643, 644 – AMP-PNP, 122, 123 a-cyano‐4-hydroxycinnamate, 35 Drosophila, 248 – asymmetry, 122 Cyclophilin D, 719 Dual Photon NADH Spectroscopy – electron microscopy, 120, 124, Cyclosporin, 9 Fluorescence, 79, 85, 86 125

Cytochrome EGLN1, 776 –F1 a3b3g, 123

– cytochrome a, 94, 95 EGLN2, 776 –F1 crystal structure, 122, 123

– cytochrome a3, 95, 102 EGLN3, 776 – hexamer, 122, 125 – cytochrome b, 69, 70, 94, 97, 101, Elasticity coefficients, 870, 871 F1Fo ATP synthase, 120–122, 126, 128 102, 107, 109 Electron transferring flavoprotein Facilitated diffusion, 645, 646

– , (ETF), 99, 100 F-actin, 242 Cytochrome c, 520 (ETC), 361, Factor inhibiting HIF‐1 (FIH–1), 777 – mechanisms of release from 550, 557, 559, 560 Fasting. See Starvation mitochondria, 707, 708 Electron transport, 877–884 Fatty acids, See Arachidonic acid – role in apoptosis, 705, 707, 708 – oxidative phosphorylation, – afterischemia-reperfusion, 417, 418 , 879, 880, 882 878–883 – ATP consumption – and cell signaling, 495, 496 – respiratory chain, 881–883 – brain oxidation, 406 – in vivo regulation by nitric oxide Embden-Meyerhof pathway, 772 – concentrations, brain, 404 of, 497–499 Endogenous fluorescence, 322–325, 335 – docosahexaenoic, 403, 406, 408, – persistent inhibition by Endoplasmic reticulum 409, 418 peroxynitrite, 494, 495 –Ca2+ release channels, 626 – free, 163, 168 – reversible inhibition by nitric – high Ca2+ microdomain – for measuring brain fatty acid oxide, 493 – negative feedback inhibition kinetics, 412 Cytochrome c oxidase, complex IV, 526, by Ca2+ of, 623, 626, 628 – half-lives brain phospholipids, 528–530, 536 – interaction with 403, 408 – inhibition by NO, 523, 528, 530, mitochondria, 618 – intratissue injection 535, 536 – phospholipid transfer, 629, 630 radiotracers, 403 – kM of, 536 – in the mitochondria associated – intravenous injection Cytochrome oxidase, 775 membrane fraction, 625 radiotracers, 409 – oxidation, 361, 362 – regulation of structure by – palmitic, 406, 408, 09, 417, 418 Cytochrome P450 reductase, 53 – Ras family GTPases, 621 – polyunsaturated, 168 Dantrolene, 31 Endothelial cells, 120 – radioactive, intravenous, 407 Data collection, 893 Energy, See ATP – recycling in phospholipids, Definitions(very vague term) Energy metabolism 407–409 Delayed calcium deregulation (DCD), – of cerebral cortex slices, 21 Fibroblast growth factor 2 (FGF‐2), 780 532 – age related changes, 22, 23 Flavoprotein Index 917

– biphasic fluorescence, 324, 325 – physiological relevance, 250–252 – reuptake, 190, 191 –Ca2+-dependence, 325, 330 – roles of, 247, 248 – transport, 149, 162 – fluorescence imaging in – vesicular glutamate uptake, Glutamatergic neurotransmission, 66, anesthetized animals, 332 245–247 79–86 – fluorescence imaging in cortical Gene knockouts, 797–799, 801, 804 Glutamine, 184, 187–192, 474, 479, 480, slices, 332 Genomics, 890, 893, 898, 899, 907 590–596, 601–606, 609, 610 – lipoamide dehydrogenase, 324 GFP-based fluorescence probe, 337 – transport, 161 Flt‐1, 779 Gleevec, 900 Glutamine cycle, 65, 66, 80, 81, 83 Fluorescent probes Glia, 590, 592–596, 600, 601, 605, 606, Glutamine synthetase, 184, 188, 191 – limitations, 523 607–609 Glutamine-glutamate-cycle, 200, 213, – specificity, 523, 525 – in anaplerosis, 188–191 216, 222–228 Flux Balance Analysis (FBA), 883 Glial-derived nitric oxide, 499, 500 Glutathione (GSH) Flux, 891–893, 895, 899, 900, 904 Glioblastoma, 905 – peroxidase, 704, 706, 707 Fo Global cerebral ischemia, 780 – reductase, 706, 707, 710 – a subunit, 125–127, 129 Glucogenic amino acids – oxidized (GSSG), 521 – A6L, 121, 126 – in anaplerotic reactions, 184, 187, Glutathione, 42, 49, 51 – ATP6, 120, 121, 129 189–191 Glyceraldehyde phosphate – b subunits, 123, 124, 126–128 – serum levels of, 188 dehydrogenase (GAPDH), 242 – c subunit ring, 125, 126 Gluconeogenesis Glyceraldehyde phosphate isomerase, 242 – c subunit, 125–127 – and alanine, 159, 162 Glyceraldehyde‐3-phosphate – D61, 125, 126 – and aspartate, 159 dehydrogenase (GAPDH), 35, 657, – deprotonation, 126 – and glutamate, 162 772, 773, 776 – dimerization process, 127 – and glutamine, 162 – role of nitric oxide in the – E65, 125, 126 – and lactate, 154 regulation of, 506 – FoI-PVP(b), 121, 127 Glucose Glycogen, 772–775 – mitochondrial DNA, 121 – and starvation, 139, 143, 145, – and ATP yield, 142, 145, 146, 151, – NMR, 125 146, 155, 156, 162–164, 166, 158 – oligomer, 120, 126 167, 169 – phosphorylase, 773

– OSCP, 121, 128 – carbon dioxide (CO2) production – storage in astrocytes, 156, 157 – proton translocation, 120, 122, from, 151, 152 – storage in neurons, 156, 157 124–126 – oxidation, 163, 164, 167–169 – synthesis, 142, 159, 160, 162, 652 – protonation, 126 Glucose metabolism, 199–212 – synthase, 159, 160 – two half channels, 125, 126 Glucose oxidation, 201, 202, 206–209 Glycogenolysis, 772, 774 Free radicals, 307–312, 314, 315 Glucose uptake – and glucose release, 158, 159 Friedrich’s ataxia, 538, 539 – activation by nitric oxide in – and lactate release, 143, 146, 149, Fructose, 156, 159, 160 astrocytes of, 502–504 150, 154, 155, 169 Fructose‐1,6-bisphosphatase(FBP), – main carriers in brain, 501, 502 – in astrocytes, 156, 157 156, 159 Glucose, 65, 67, 191, 298, 300–304, 307, Glycolysis, 14, 202, 204, 206–208, 222, Functional brain imaging 772–776, 779, 781, 782 228–230, 477, 481, 881, 883, 884, –Ca2+ indicator, 323, 325 – 13C-labeled, 188–190 892, 900, 903, 905 – intrinsic signal, 323 – radiolabeled in tracer studies, – 6-Phosphofructo‐1-kinase – optical recording, 323 189, 190 (PFK1) activation by nitric oxide – pH Indicator, 324 Glucose‐6-phosphatase, 54, 158, 159 and, 508 – voltage-sensitive dyes, 323 Glucose‐6-phosphate dehydrogenase, – 6-Phosphofructo‐2-kinase Functional genomics, 898, 899 42–44, 47–49, 54 (PFK2) activation by nitric oxide Functional Magnetic Resonance GLUT1, 774, 779, 781, 783 and, 508 Imaging, 64, 79 GLUT‐3, 781 – during activation, 384–386 G protein, 253 Glutamate accumulation – nitric oxide in the regulation of, GABA, 187, 190, 191, 891, 899 – content in synaptic vesicles 506–508 GABAergic neurotransmission within synaptosomes, 244 – regulation by 5‘-AMP-activated (not found) – release from synaptosomes, protein kinase (AMPK), 508 GAPDH/3-PGK, in synaptic functions 244, 245 Glycolytic enzymes, 242, 649 – complex formation, 245 – uptake into synaptic vesicles, 244 Glycolytic phosphotransfer – coupling to ATPases and ion Glutamate, 184, 188, 189, 192, 470, 473, enzymes, 643 channels, 248–250 474, 478, 479, 480, 481, 590–611 Glycolytic phosphotransfer – pathophysiological implications, – drainage of TCA cycle through system, 644 252, 253 release, 187 Growth factor signaling, 534 918 Index

H+ pump ATPase–VGLUT system, 253 Hypoxia/ischemia Ischemia, 20, 145, 156–160, 480, 481, Heme oxygenase, 53, 534 – role of glial cells, 499, 500 528, 557, 561, 562 Hemodynamic responses, 335 Hypoxia-inducible factor‐1 (HIF‐1), – effects on synaptic transmission, – comparison with fluorescence 651, 772, 775–783 26–28 imaging, 330 Hypoxic response element (HRE), 772, – irreversible damage after, 25 – nitric oxide, 331 775, 776, 778, 781, 782 Ischemia, cerebral – non-invasive brain imaging, 330 IF1 – arachidonic acid, increased Heterogeneity of ATP and ADP – DpH+, 120, 127 incorporation on reperfusion, diffusion and compartmentation of – anoxia, 127 417, 418 adenine nucleotides, 835–837 – ATP synthase dimer, 128 – ATP debt, 407, 418, 419 Heteroplasmy, 880 – energy depletion, 128 – release fatty acids from Hexadecanol – histidine 49 (His49), 127 phospholipids by phospholipases, – tritiated, for measuring brain – IF1 dimer, 128 417 ether phospholipid synthesis, 416 – IF1:F1 complex, 128 – therapeutic approaches, 418, 419 Hexokinase (HK), 160, 164, 358, 772, – inhibitory action, 128 Ischemic preconditioning (IPC), 534, 773, 776 – ischemia, 127 537, 538 HIF prolyl hydroxylases, 776 – Luft’s disease, 128 HIF‐1a, 775, 777–780, 783 – natural inhibitor protein, 127 (NADP+-dependent), 50 Hif‐1a, hypoxia-inducible factor, – neoplastic cells, 128 Isotopomer, 891, 892 + 536–537 – pathophysiology, 128 K ATP channel, 535, 537, 538

HIF‐1b/ARNT1, 775 – pH dependence, 127 KATP channel, 651, 652 HIF‐2a/EPAS1, 775 – pH independent binding, 128 Ketogenic diet, 139, 145, 162, 164, HIF‐3a, 775 – pH, 127, 128 169 Hippocampal slices, 145, 146, 155, 156, – tumor cell growth, 128 3-Ketoacid-CoA transferase, 163, 166 158, 160, 165, See also Brain slices Immunoprecipitation technique, 243 a-Ketoglutarate, 139, 161, 162 History, 900, 902, 903 Import of mitochondrial proteins Ketone bodies, 882, See also HPH1, 776 – internal targeting signal of, acetoacetate, b-hydroxybutyrate HPH2, 776 107, 108 – and developing brain, 145, 165, HPH3, 776 – N-terminal cleavable 166, 168 HPLC, 892, 894–896, 901 presequences of, 107 – and suckling stage, 154, 165, 166 Huntington’s disease (HD), 538, 890, – post-translational, 94, 97, 107, 108 – during starvation, 166, 167, 169 892, 906 – in neuronal function and energy – glucose-sparing effect of, 163, HUVEC, 120 metabolism 164, 169

Hydrogen peroxide (H2O2), 521 Incorporation coefficient, 405 – metabolism of, 165 Hydrogen turnover, 75 Informatics, 895–897, 904, 907 – transport of, 164, See also ˙ Hydroperoxyl radical (HO2 ), 521 Inhibitors, 520, 525–528, 534, 538, 539 Monocarboxylate transporters b-Hydroxybutyrate Inhibitory postsynaptic potential – utilization of, 163–169 (3-hydroxybutyrate), See also Ketone (IPSP), 24 a-KGDH, a-ketoglutarate bodies Insulin-like growth factor 1 (IGF‐1), dehydrogenase, 527, 528 – and ATP, 165 780, 782 Krebs cycle, 891, 892, 903 – and phosphocreatine, 165 Insulin-like growth factor 2 (IGF‐2), 780 Krebs–Ringer buffer (KRB), 244 b-Hydroxybutyrate dehydrogenase, Integrated cellular phosphotransfer Kynurenic acid, 891, 892 166 network, 644 Lactate, 202, 204–208, 216–219, 3-Hydroxy‐3-methylglutaryl-CoA, 52 Intracellular energetic units, 822, 823 221–230, 590, 593–601, 607, 608, Hyperammonemia, 480 Intracellular enzymatic networks 610, 772–775, 781 Hyperinsulinemia, 560 – facilitated diffusion, 645, 646 – and developing brain, 148, 154 Hypermetabolism, 559 – ligand conduction, 647, 648 – and hypoglycemia, 143, 154–156, Hypoglycemia, 20, 24, 28, 242, 253, – metabolite channeling, 646 159, 163, 164, 169 300, 301 – reaction-diffusion, 646, 647 – and long-term potentiation – and starvation, 139, 143, – simple diffusion, 645 (LTP), 145, See also Synaptic 145–147, 153–156 Intracellular, 199, 201, 208, 215, 216, plasticity Hypothermia, 32 223, 226–230 – and paired-pulse facilitation, 145, Hypothesis generation, 902, 903 Iodoacetate, 250, 252 See also Synaptic plasticity

Hypoxia, 20, 32, 156–160, 162, 298, Ion channels, 535 – carbon dioxide (CO2) production 300–302, 304–307, 309, 480,481, 536, Ion homeostasis, 347, 348 from, 151, 152, 156 537, 772, 775–782 Ionotropic, 900 – metabolism, 142, 143, 151 Index 919

– shuttle, 148–151, 153, 477, 478 Membrane potential (Dcm), 520, 528, – anti-oxidant systems in, 709 – transport, 144, 145, 159, 474, 531 – biogenesis, 789–805 477–480, See also Membranes, See Aminophospholipids – calcium circuit, 7–8 Monocarboxylate transporters – Asymmetries, 402, 409–411, 417, – calcium uniporter, 7, 9, 13 – utilization, 148, 151, 169 420 – carnitine-O-palmitoyl Lactate dehydogenase (LDH), 242, 359, – remodeling and reacylation of transferase, 406 360, 773 phospholipids, 419 – dehydrogenases in, 706–708 – and reversible equilibrium, 143, – synaptic, 420 – DNA in, 270, 283 147, 148, 152, 153 Metabolic compartmentation – fission of, 265, 266, 270, 282, 285 – LDH‐1, 143, 144, 149, 151 – during activation, 388–391 – fusion of, 266, 270 – LDH‐5, 143, 144 Metabolic control analysis (MCA) – gene organization, 790 Lactate shuttle, 86, 774 – connectivity theorem, 880 – heteroplasmy, 791 Leucine, 223–228 – control coefficient, 878–880 – inheritance, 790 Ligand conduction, 647, 648 – elasticity coefficient, 879 – isolation, 531 Lipid oxidation, 535 – summation theorem – localization of, 268, 274 Lipids and oxidant stress, 314, 315 Metabolic control analysis, MCA, – membrane permeability Liver, 157, 163, 165, 167 868–872 transition, 708 L-type calcium blocker, See Nimodipine Metabolic coupling, 79, 80, 83, 85 – membrane potential indicators, Luciferin/luciferase method, 245 Metabolic function, 531 11, 13 Malate, 162, 186, 188 Metabolic perturbations, 20 – mitochondrial NOS, 712 – equilibration with fumarate, 185, Metabolic syndrome, 651 – motility of, 268, 270, 276, 287 188, 190 Metabolism, 402, 403, 405, 406, 417, – mtDNA, 791, 795–799, 801 – product of pyruvate 419, 420 – nitric oxide and cytochrome c carboxylation, 184, 187, 189, 190 – anaplerosis, 571, 578 oxidase, 493 Malic enzyme, 188–191 – ATP production, 405, 406, 420 – oogenesis, 791, 792 – mutation of in epilepsy, 192 – baseline (stages 0‐1), 350 – oxidative phosphorylation, 266, – Reaction catalyzed by, 186, 187 – disruption ischemia, 417 275, 276 Malic enzyme, 50 – elevated (stages 3‐4), 350, 351 – oxidative phosphorylation, 406, Mannose, 159, 160 – human, compared with rat, 406 417 Mannose‐6-phosphate isomerase, 160 – malate, 571, 575, 580 – permeability transition, 9 MAP kinases, mitogen activated protein – normal (default), 350, 351 – peroxynitrite and cytochrome c kinases, 537 – oxygen consumption, 405, 406 oxidase, 494, 495 Mass spectrometry coupled to gas – P/O ratio, 405, 406 – pH gradient, 10 Chromatography (not found) – resting (stage 2), 350 – proton circuit, 6–7 Mass spectrometry (MS), 739, 746–750, – succinate, 574, 575, 578 – protonophores, 14 893–896, 898, 899, 901 – transamination, 571, 578, 579 – reactive oxygen species Massive depolarization-induced – tricarboxylic acid cycle, 574, generation (ROS), 706–709, 711, conduction block, 24 576–578 713–715 Mathematical modeling Metabolite channeling, 646 – replication, 792, 793 – basic principles, 823–826 Metabolite cycling, 368 – role in neuronal apoptotic death, – modeling reactions in Metabolites, 23 708 intracellular medium: the Metabolome, 893, 895, 898–901 – sodium circuit, 7–9 problem of macromolecular Metabolomics society, 907 – sodium/calcium exchanger, crowding, 826 Metabolomics, 889–907 7–9, 13 Matrix processing peptidases (MPPs) Metabotropic, 900, 904 – sodium/proton exchanger, 7–9 – Pitrilysin family, 102 Metalloproteases, 535 – structure, 790 M-CK gene, 652 Metastasis, of cancer cells, 535 – superoxide production, 706–709 MCT1, 774 Methylmalonyl‐CoA, 187 – targeted antioxidants, 525, 539 Measurements Microglia, 139 – transcription, 793, 794 – chemiluminescence, 524 Microsomes – turnover, 269, 282 – end points vs. kinetics, 526 Migration, 535 Mitochondrial biogenesis, 563 – fluorescence, 523, 524, 526 Mitochondria, 430, 436, 441, 442, – ATP, 550, 557–562 – of RNS, 528 445–448, 450, 455–457, 668–689 – calcium dysregulation, 557 – of ROS, 524, 526 – adenine nucleotide translocator, 5 – electrochemical gradient, 550 Membrane permeability transition, 704, – adherens complex, in, 264, – electron transport chain (ETC), 708, 709, 714, 715, 719, 721, 723 278–279 550, 557, 559, 560 920 Index

– energy metabolism, 562, 563 – pH gradient across, 626 Modeling of the functional coupling 2+ –F0F1-ATPase, 557 – regulation by Ca , 621, 626, mechanisms in mitochondria – mitochondrial membrane 628 dynamic compartmentation,

potential (cm), 558, 560, 562 – regulation by GTPases, 618, 621 826–828 – pH gradient (DpH), 560 – yeast and drosophila – direct transfer mechanism, – proton electrochemical gradient mutants, 621 828–830 (Dp), 550 Mitochondrial pathologies – phenomenological models, 834 – tricarboxylic acid (TCA) cycle, 559 – 3-hydroxyglutarate, 129 – probability model of MtCK to Mitochondrial diseases, 878, 880, 884 – Alzheimer’s disease, 129 ANT coupling, 830, 831 – CPEO (Chronic Progressive – ataxia, 129 – the main results of probability External Ophtalmoplegia), 880 – Batten disease, 129 model, 831, 832 – MELAS (Mitochondrial – brain, 129 – thermodynamically consistent encepholopathy, lactic acidosis – ceroid lipofuscinosis, 129 model of MtCK-ANT coupling, and stroke like episodes), 880 – excitotoxicity, 129 832–834 – MERRF (Myoclonic epilepsy with – MILS, 129 Modeling the mitochondrial respiration ragged red fibers), 880 – mtDNA, 129 controlled by Frank-Starling Mitochondrial DNA, 880–882 – mutations, 129 mechanism under conditions of – heteroplasmy of, 109 – NARP, 129 metabolic stability – homoplasmy of, 109 – neurodegeneration, 129 – metabolic control analysis of the – maternal inheritance of, 109 – neuronal degeneration, 129 factors of regulation, 842–846 – mutations of, 109–111 – NMDA receptor, 129 Molecular chaperones, 632 – replicative segregation of, 109 – retinitis pigmentosa, 129 – role in folding of nascent Mitochondrial membrane potential Mitochondrial uncoupling proteins, 550 polypeptides, 620, 632, 633

(cm), 558, 560, 562 – regulation of activity (MAO), 527, – role of nitric oxide in, 496, 497 – free fatty acids, 551, 559 529, 531

Mitochondrial morphology –KATP channels, 560, 561 Monocarboxylate transporters (MCTs), – fusion/fission – lipolysis, 559 474–480 – adenine nucleotide – lipid peroxidation, 558, 560 – in astrocytes, 164 translocase, 622 – norepinephrine, 558, 559 – and ketone bodies, 144 – ATP microdomain – ubiquinone, 557, 558, 562 – and lactate, 144, 169 between, 625 – regulation of expression – in neurons, 164 –Ca2+ uniporter, regulation of – alternative initiation sites, 551 – MCT1, 144, 145, 164 metabolism by, 626, 627, 629 – arachidonic acid 561 – MCT2, 164 –Ca2+ uniporter, shaping – calorie restriction, 560 – MCT4, 164 global Ca2+ signal by, 627 – fasting and high-fat diets, 551 – and pyruvate, 145, 164 – during apoptosis, 630 – lipopolysaccharide (LPS), 562 – and starvation, 164 – outer membrane, voltage – mRNA stability, 551 MPP+, MPTP, 550, 562 dependent anion channel – post-transcriptional mRNA/protein stability, 551 – evolution of machinery of, –PPAR-g, 561 Mu¨ller cells, 145, 149 618, 619, 621 – translational, 551 Multiple sclerosis, 55, 538 – interaction with creatine – involvement in systemic disease Muscarinic receptor loops, 311 kinase, 623–625 states, 560 Muscarinic receptors, 309–312, 314 – interaction with – obesity, 558, 560 Myo-inositol hexokinase, 625 – physiological roles in – deuterated, for measuring – localization at ER- metabolism, 558 phosphatidylinositol cycle, 420

mitochondria contacts, – thermogenesis, 550, 559–561 N2O-anesthetized brain, 21 625, 632 – tissue distribution Na+/K+-ATPase pump activity, 249 –membranepotentialacross,626 – brain, 562 NaCl solubilization experiments, 243, –Na+/Ca2+ (mNCX) and H+/ – Brown adipose tissue (BAT), 244 Ca2+ (mHCX) exchanger, 627 550 NAD(P)H – permeability transition pore Mitochondrially encoded subunits, 128 – electron donor in oxidative opening, during apoptosis Mitochondrial-nuclear metabolism, 324 and necrosis, 625 intercommunication, 648–651 – electron donor in reductive – proteome, 633 Mitosox red, 524 biosynthesis, 324 – permeabilization of, during Modeling – Krebs-cycle dehydrogenase, 324 apoptosis, 623 – electron transport model, 882–884 NAD+, NADH, 520, 524, 527–529 – inner membrane – NET model, 882 NADH balance, 85 Index 921

NADH/NAD+ ratio, 142, 145, 150, 155 – metabolic properties, 363, 364 –[13C]glutamate, 575–580 NADPH oxidase, 52, 53 – oxidative capacity, 365, 368 – 13C spectroscopy, 570, 574, NADPH, 42, 44–55, 184, 187, 189 – synapses of, 407, 408 575, 580 Necrosis, 684, 687 Neuroprotection, 562 Nuclear respiratory factors, 795–798 NET model (Non-Equilibrium – anti-apoptotic strategies for, 713 Nuclear-coded proteins, 648 Thermodynamic Model), 882 – anti-apoptotic, 563 Nuclearly encoded subunits, 128 Neural activity, See Synaptic – antioxidant defense systems, 563 NXXS(T)K motif, 248 transmission – dopaminergic neurotoxicity, 562 Obesity, 558, 560 Neural plasticity – Bcl‐2 family proteins in, 720, 721 Oda5p protein, 643 – induction after cortical – 1-methyl‐4-phenyl‐1,2,5,6 Oligodendrocytes, 148, 165, 168 stimulation, 332 tetrahydropyridine (MPTP), 550, Oligomycin, 120, 127, 244, 245, 250–252 – induction after learning, 332 562 Optic nerve, 145, 156, 159–162, 165 – long-term depression, 332 – mitochondria in, 721 Orthodynamic and antidromic – long-term potentiation, 332 – role of nitric oxide in, 499 stimulation, 20 – spatial distribution of, 332 – role of peroxynitrite in, 499, 504, Ouabain, 14 Neurodegeneration, 538 505 2-oxoglutarate, 777 – apoptosis in, 717, 720, 723 Neurotoxicity Oxaloacetate, 142, 155, 162, 185, 187, 190 – oxidative stress in, 705 – by nitric oxide, 499 – concentration in brain, 186 Neurodegenerative diseases, 35, 253, – by peroxynitrite, 499 – product of pyruvate 561, 645 Neurotransmission, 184, 190–192 carboxylation, 184, 189 – Alzheimer’s disease, 54, 538, 562, Nimodipine, 31, 33 18O-labeling technique, 648 704, 890–892, 902 Nitration, 709, 714 b‐oxidation of fatty acids, 878, 883 – Bcl‐2 family proteins in, 717, 718, Nitric oxide Oxidative 719–721 – biochemistry of, and RNS, 523, – phosphorylation, 706, 708, – Ischemia, 562 528, 530 714, 723 – mitochondrial dysfunction in, – mtNOS, mitochondrial NOS, 530 – stress, 705–715 704, 705 – physiology vs. pathology, 539 Oxidative metabolism, 65, 67, 80, 83, 85 – Parkinson’ disease, 529, 531, 538, – signaling, 536 Oxidative phosphorylation, 878–883 562, 717, 721, 890, 892, 902 – synthase, NOS, 710, 712 – consume of oxygen in, 94 Neurological function, 803–805 – biosynthesis of, 488 – during activation, 386–388 – fragile X syndrome, 803 Nitric oxide synthase (NOS) – oxidative damage in, 94 – glutamate receptor, 804 – endothelial isoform (eNOS or – reduction of oxygen in, 104 – nitric oxide synthase, 804 NOS3), 488, 489, 503, 504 Oxidative stress, 309, 559, 562, 563, – NRF‐2 and cytochrome – inducible isoform (iNOS or 668, 672, 673, 679, 680, 681, 684, 685, oxidase, 804 NOS2), 488, 489, 492, 495, 499, 687, 688 À Neuron-glia interaction, 201, 213 502, 504, 505 O2 (Superoxide anion), 521, 522 Neurons, 65, 67, 71, 72, 74, 79, 80, – neuronal isoform (nNOS or Oxygen, 298–301, 304, 305, 307, 308 83–86, 143–145, 148–159, 161, 162, NOS1), 488, 489, 497–499 – as substrate for ROS, 536 164, 165, 168, 199–230, 531, 538, Nitric oxide synthase, 52 – concentration, 522

590–597, 599, 600–602, 605–609, 668, Nitric oxide, 380, 382, 383, 780, 781 – cytochrome oxidase, Km for, 677, 678, 685, 687, 689, 881, 882, 884 Nitrosylation, 714 709, 713 – in anaplerosis, 186–192 Nm23 gene, 650 – microvascular – brain, 413, 414, 420 N-methyl-D-aspartate blocker, 31 – role in superoxide generation, 706 – cultured NMRS, 73, 79189, 190, 893–897, – sensing in hypoxia, 536, 537 – myo-inositol exposure, 413, 899–901, 904, 905 – tissue tension in cerebral 414, 420 Nomenclature, 521 cortex, 709 – phosphatidylinositol cycle, Nrf‐2, nuclear respiratory factor 2, 535 – regulation of, 378 rate in, 411 Nuclear factorkB (NFkB), 534 Oxygen-dependent degradation – death following Nuclear Magnetic Resonance Imaging, (ODD), 776, 777 – ATP depletion, 417 74–79 p53, 719, 720, 722 – Ischemia, 410, 418 Nuclear Magnetic Resonance Parkinson’ disease (PD), See – functional properties, 363 Spectroscopy, See NMRS Neurodegenerative diseases – glycolytic capacity, 369 Nuclear magnetic resonance, 201–207, PARP, poly ADP-ribose – and lactate dehydrogenase 209, 211, 213, 217–219, 221, 222, polymerase, 532 (LDH), 143, 144, 149–151, 153 226, 230, 570, 577, 578 PARP‐1, 714, 715, 719, 721, 722 – monocarboxylate transporters in, –[13C]acetate, 574, 575 Pasteur effect, 772, 783 144, 164 –[13C]glucose, 570, 574–578 Pathways, 891–895, 898, 900, 903–905 922 Index

Pentose phosphate pathway, 42, 43, 47, Phosphoglycerate kinase (PGK), 35, Population spike, 19, 25–27 50, 51, 53–54 773, 776 Porin-bound hexokinase, 649 – Glucose‐6-phosphate Phosphoglycerate mutase (PGM), 773 Positron Emission Tomography, 73–74, dehydrogenase, 505 Phospholipases 79, 85 – regulation by nitric oxide, 504, 506 – activated, in ischemia, 418 Postsynaptic density (PSD), 242

– regulation by peroxynitrite, – phospholipase A2, 402, 407, 408, Post-translational modifications, 738, 504, 506 417–419 739, 741, 742, 746, 749, 760, 761 – and sulfhydryl groups, – phospholipase C, 402, 411, 412, 414 – review, 749, 754 489, 490 – stereospecific selectivity, 407 Potassium, 347, 348, 350, 363, 370, 380, – and 3-nitro-tyrosine, 490 Phospholipids 382, 383, 431–436 – in neuroprotection, 504, 505 – action of phospholipases on, 402, Preconditioning, 534, 537–539 PEPCK, 186, 187, 189, 190 408, 417 Probability approach in description of Peroxide, 49, 51 – aminophospholipids, 406, enzymes and transporters, 849–852 Peroxisome proliferator activated 409–411, 417, 420 Prolyl hydroxylase domain-containing receptor (PPAR), 535 – ATP stoichiometry, 405, 406, 410, proteins, 776 Peroxynitrite, 521, 522, 532 411, 415 Propionic academia, 192 pH – de novo synthesis, 404, 407, 411, Propionyl‐CoA carboxylase – changes, 470–474 411–414, 419 – deficiency of, 192 – regulation, 474–477 – disrupted in ischemia, 417, 418 – reaction catalyzed by, 187 – sensitive dyes, 471, 472 – ether phospholipids Propionyl‐CoA, 187, 192 – sensitive K+ channels, 476 – membrane asymmetries, 406, – metabolite of amino acids, 186 – sensitive microelectrodes, 471 409–411, 417, 420 – substrate in carboxylation pH gradient (DpH), 560 – rate equations (not found) reaction, 187 Pharmacometabolomics, 904, 905 – role translocase, 410 Prostanoids, 380, 383 PHD1, 776, 778 – biosynthetic pathways, 415 Protein kinases, cell signaling, 535 PHD2, 776, 778 – definitions of, 414 – MAPKs, 534 PHD3, 776, 778 – synthesis and ATP – PDH, , 528 Phenazine methosulfate, 48 consumption rates – PHD, prolyl-hydroxylase Phosphatidylinositol (PI) cycle microsomes, 414–416 enzymes, 537 – as precursor in cultured – phosphatidylcholine, 408 – PKA, 527, 534 neurons, 413 – phosphatidylethanolamine, 408, – PKC, 534, 537 – ATP requirement for, 411–414 410–411 – proton leak, 528 – biosynthetic pathway, 412 – phosphatidylinositol, cycle, – PT Pore, permeability transition – de novo synthesis, 411, 413, 414 411–414 pore, 523, 530, 532 – extrapolation from platelets, 420 – phosphatidylserine, 410, Protein phosphorylation, 247, 248 – maintaining phosphorylation state 411, 417 – cAMP dependent, 99 – myo-inositol, 411–414 – turnover and half-lives of Protein trafficking, 621 – phospholipase C in, 411, 412, 414 components, 403–405 Proteomics, 738–763, 890, 893, 899, 907 Phosphocreatine Phosphorylase, 158, 159, 167 – brain metabolism, 759–761 – hydrolysis of – a, 157–158 Proton – during activation, 384 – b, 157–158 – concentration, 471, 472, 476 – kinase, 357 Phosphotransfer networks, 642 – equilibrium potential, 471 Phosphocreatine kinase system, for – based metabolic signaling, – gradient, 471, 476–477, 480 maintaining ATP, 20 651–654 – permeable channels, 476 Phosphocreatine, 883 – in mitochondrial-nuclear – sequestration, 471, 473 Phosphoenolpyruvate carboxykinase, intercommunication, 648–651 – signaling, 470, 476 See PEPCK – in processing and integrating Proton electrochemical gradient (Dp), Phosphofructokinase (PFK), 35, cellular information, 654–657 550 772–774, 776 Pi carrier, 879, 881 Proton pathways, 104, 105 Phosphofructokinase, 163, 164, 358 Plasma membrane, 410, 411 Proton transfer 6-Phosphogluconate dehydrogenase, Platelet-activating factor (PAF), – mechanism of, 94, 102–104 42, 43, 45, 49 417, 419 – redox centers, 104, 106 6-Phosphogluconolactonase, 42, 43, 45, Platelets Purkinje neurons, 139, 149 97, 101, 102 – extrapolation to brain, 420 Pyruvate – cytochrome c, 94, 96, 97, 100, 102 – phosphorylation of – incarboxylationreactions,184–187 Phosphoglucose isomerase (PGI), phosphatidylinositides, 412, 413 – pyruvate dehydrogenase 773, 776 PMF, 120 complex, 361 Index 923

– radiolabeled, 188, 189 Respiration, 6, 7, 10, 11, 14 – outer membrane, 264, 267, 273, – recycling, 189, 190 Respiratory chain complexes, 94, 97, 279, 280 , 142, 155, 159, 107, 108 – tomography, 263, 264 187–191, 884 Respiratory chain, 881–883 Subcellular compartmentation, 66, 78 – in astrocytes, 155, 159 – respiratory complexes, 879–881, Subcellular transfer of reducing – deficiency of, 191, 192 884 equivalents, 65, 67, 72, 85, 86 – reaction catalyzed by, 186 Respiratory complexes, 879–881, 884 Substrate transport Pyruvate carboxylation, 185, 187–191 Reuptake, 301 – during activation, 377–382 – relation to brain activity, 189 Ribulose‐5-phosphate isomerase, 42, – glucose, 352, 353 – time dependence, 194(found in 43, 45 – monocarboxylic acids, 353–355 reference) Ribulose‐5-phosphate, 42, 43, 45, 47 – oxygen, 355 Pyruvate carrier, 879, 881 Ribulose‐5-phosphate‐3-epimerase, 42 – tricarboxylic acid cycle, 357 Pyruvate compartmentation, 83, – roles in glucose homeostasis in Succinate, 162 85, 86 the brain Suckling stage, 154, 165, 166 Pyruvate dehydrogenase complex Ryanodine receptor (RyR), 535 Summation theorem, 878, 879, 881 (PDHC), 142, 154, 155, 163, 164, Scavengers of ROS & RNS, 525 Superoxide, 550, 558, 560, 708, 709, 167, 168 ScCKmit isoforms, 649 711–713 – and starvation, 167 Sciatica, 904 – superoxide dismutase (SOD), Pyruvate dehydrogenase kinase (PDH SDS-PAGE/Western blotting, 245, 246 706, 714 kinase), 163, 164, 167 Seizure, 720, 721 Superoxide Dismutase (SOD), 521, Pyruvate dehydrogenase phosphorylase Sensitivity theory, 868 522, 525 (PDH phosphorylase), 167 SFRBM, 522 – Copper/Zinc SOD, 521, 523, Pyruvate dehydrogenase, 714, 884 Signaling, 523, 533–537 533, 538 Pyruvate kinase (PK), 242, 772, Sodium, 431–436 – Manganese SOD, 522 773, 776 Sodium-bicarbonate cotransporter Supervised approaches, 896 Pyruvate recycling, 213, 216–222, (NBC), 473, 474, 476–478 Synaptic activity, 470, 474, 478 228, 230 Sodium-dependent chloride/ Synaptic plasticity Pyruvate, 142–156, 158, 159, 162–165, bicarbonate exchanger (NCB), 474 – and lactate, 145 168, 201, 203–213, 216–225, Sodium-hydrogen exchanger (NHE), – and pyruvate, 145 228–230, 772–774, 780 471, 474–478, 480 Synaptic transmission, 145, 165, 242 – and long-term potentiation, 145, Solute carrier protein 25 (SLC25), 550 – effects of anoxia and ischemia, See also Synaptic plasticity Sphingomyelin, 314 26–28 – carboxylation, 155 Spinal stenosis, 905 – and fructose, 145 – transport, 155, 156, See also Stable Isotope-based Dynamic – and b-hydroxybutyrate, 165 Monocarboxylate transporters Metabolic Profiling (SIDMAP), – and lactate, 145 Reaction potential, 386, 387 865–867 – long-term potentiation of, 20 Reactive Nitrogen Species (RNS), 520, Standards (data reporting), 895–897, 907 – and mannose, 145 521, 705–709, 711, 713–715, 721 Starvation, 143, 145, 147, 154, 155, – and pyruvate, 145 Reactive Oxygen Species (ROS), 44, 520, 162–164, 166–168, See also Fasting – and relation between glycotic 521, 527–530, 532, 533, 536 – and hypoglycemia, 146, 153, 155, metabolism, 28–35 – detoxification of, 706 156, 162–164 – and relation between oxidative – mitochondrial generation of, – and ketone bodies, 163, 166 energy metabolism, 23–28 707, 708 – enzyme regulation during, 155 Synaptic vesicle-associated glycolytic – toxicity, 706 Stroke, 537, 538, 710, 711, 717, 722 ATP-generating enzymes Reactive oxygen species Structure – complex formation of GAPDH and generation, 560 – condensed, 279 3-PGK on synaptic vesicles, 245 – complex I and III, 560 – contact site, 264, 267, 268 – coupling of glycolysis to ATPases – oxidative stress, 559, 562, 563 – crista junction, 264–268 and ion channels, 248–250 – redox-sensitive, 560, 562 – cristae, 264–267, 275, 279, 281, – other roles of GAPDH/3-PGK, – regulation by UCP, 560 282, 286, 288 247, 248 – superoxide, 558, 560 – heterogeneity of, 262, 270, 271, – pathophysiological implications, Receptors, 301, 307, 309, 310, 313 273, 275, 276, 281, 285, 286 252, 253 Redox signaling, 523, 533, 535, 536 – inner membrane, 264–268, 270, – physiological relevance, 250–252 Red-ox switch/coupling, 83–86 282–285 – preparation methods, 243–245 Regulation of weight and body – matrix, 264, 266–268, 274, 279 – vesicular GAPDH/3-PGK- composition, 558 – network, 265, 268 coupled glutamate uptake, Release, 301, 302, 305–308 – orthodox, 279 245–247 924 Index

Synaptosomes, 161, 166, 243, 244 Transaldolase, 42, 43, 46, 55 Translational efficiency, 551 – treatment of, 252 Transcranial imaging, 337, 338 Trauma, 717 Systems biology, 861–873, 890, 895, 904 – cortical activities in mice, Tricarboxylic acid (TCA) cycle, 83–85, TCA cycle intermediates, 187, 190, 191 335, 336 199–204, 207–211, 213, 216–222, – products of anaplerosis, 184 – genetically manipulated mice, 335 225–230, 550, 559 – transport across the blood brain – in awake mice, 336 Tricarboxylic acid cycle, See TCA cycle barrier, 188, 189 – in the auditory cortex, 335 Triose phosphate isomerase (TPI), TCA cycle, 184–191, 527, 528, 529, 530, – in the somatosensory cortex, 335 773, 776 537, 883, 884, 900, 905 – in the visual cortex, 335 Tumor Tg2546 transgenic mice, 35 Transcription factor signaling, 534, 535 – and anaplerosis in brain, 192 Thapsigargen, 249 Transcription factor, 772, 775, Two-dimensional gel electrophoresis, Therapeutic strategies, 538 776, 783 739, 751, 762 Thermodynamics, 4, 5 Transcriptional activators UbCKmit isoforms, 649 – ATP hydrolysis, 5 – acting on mitochondrial Ubiquinone, 525, 527, 534, 557, – Gibbs free energy, 4–6 genes, 803 558, 562 – ion electrochemical potential – acting on nuclear genes, 797 Ubiquitin-proteosome system, 775 difference, 6 – ERRa, 797, 801 Ubisemiquinone radical, 526, 527 – mass action ratio, 4, 5 – HAP, 794, 795 UCPs, 528, 535 – Nernst equation, 10 – NRF‐1, 795–804 Uncouplers, 525, 526, 539 – proton electrochemical – NRF‐2, 796–799, 801, 803–805 Uncoupling proteins, 707  potential, 6 – Sp1, 795, 799, 804 UQ , 525, 527, 534 – redox potential, 5, 6 – specificity factors, 794, 798, 803 Vectorial ligand conduction, principle Thermogenesis, 550, 559–561 – Tfam, 791, 793, 794, 796–798, of, 647, 648 Thiamine, 46–47, 54, 55 801, 803 VEGF, 779, 780, 782 Thioredoxin reductase, 53 – YY1, 797, 799 Veratridine, 14 Threshold Transcriptional coactivators Vesicular glutamate transporter – threshold curve, 880, 881, 883, 884 – effects on mitochondrial (VGLUT), 251 – threshold effect, 881 biogenesis, 799–803 Virtual Free Radical School, 522 Tissue specificity, 881, 882 – mechanism of action, 799–802 Vitamin C, 777 TNF-a, tumor necrosis factor a, 534 – PGC‐1a, 799–803 von Hippel-Lindau tumor suppressor Toxicology, 897, 898 – PGC‐1b, 803 gene (pVHL), 776, 777, 783 Toxins – PRC, 802, 803 Wernicke-Korsakoff syndrome, 54 – 3-nitropropionic acid (3-NPA), – role in gluconeogenesis, 801 Western blot analysis, 243, 244 570, 574 Transcriptomics, 907 Whatman GF/C filters, 244 – Aminooxyacetic acid (AOAA), – unsupervised approaches, X-ray crystallograpic structure 570, 578 890, 893 – of complex III, 100, 104, 105, – Methionine sulfoximine (MSO), Transhydrogenase, 50 107–110 570, 573, 574 Transient ischemic attacks (TIAs), 23 – of complex IV, 102 – Methyl mercury (MeHg), 570, 579 Transketolase, 42, 43, 46, 54, 55 Zinc, 442–444, 456, 457