Index. BH3 mimetics, 232 Bifonazole, 141 Bone marrow apoptosis degenerative mitochondrial haplotypes, MDS role, Bromopyruvate,

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1 Index A Acquired idiopathic sideroblastic anemia (AISA), Adenine nucleotide transporter (ANT), Adenosine triphosphate (ATP) deficiency, generation, 151 production, 131 Aerobic respiration compartmentalization, 132 product regulation by p53, 144 proteins regulation cytochrome c oxidase (COX), cytochrome c oxidase 2 synthesis (SCO2), Akt kinase pathway, AMP-activated protein kinase (AMPK), 31 GTPase activating protein (GAP), 112 nutrient scarcity, phosphorylation, 113 regulation, Antineoplastic intervention, lipogenic switch AMPK activation, 48 cytotoxic effects, 49 FASN inhibition, fatty acid synthesis pathway, 46 malonyl-coa, 48 mevalonate pathway, 49 neu-n transgenic mouse model, 47 therapeutic treatments, Apoptosis aerobic respiration proteins, bromopyruvate role, 140 cancer cells, 226 GLUT 1 and GLUT 4, 140 hexokinase role, 136 mitocans role, regulation, role of p53, 132, 136 ATPase functional changes, ATP citrate lyase (ACL), 40 B BH3 mimetics, 232 Bifonazole, 141 Bone marrow apoptosis degenerative mitochondrial haplotypes, MDS role, Bromopyruvate, C Cancer cell biology process, 25 cytochrome c oxidase (COX) activity AMP activated protein kinase (AMPK), 31 frataxin levels, 30 HIF1/, mitochondrial deteriorated, 29 p53 tumor suppressor protein, 29 dichloroacetate (DCA) clinical translation in oncology,

2 282 Index congenital mitochondrial diseases treatment, preclinical work, genetic models glucose oxidation (GO), glycolysis, glycolysis genetic control Akt/PBK (protein kinase B), 28 GLUT1, 27 HIF1/, LDHA gene, 27 positron emission tomography (PET), p53 tumor suppressor protein, tumor suppressors and oncogenes, 26 hypoxia-inducible factor (HIF) activation hexokinase II (HK-II), lactate dehydrogenase isoform (LDH-M), pyruvate dehydrogenase (PDH) complex, 215 proton flux regulation anticancer drugs, 218 in mitichondria, 217 proto-oncogene, 24 pseudohypoxia, reactive oxygen species (ROS) generation Akt kinase pathway, general model apoptosis, PI3K Akt pathway, 223 residual respiratory function, thiol redox system, Warburg effect 2-deoxy-D-glucose (2DG), lonidamine, 32 metabolic characteristics, 23 Cancer therapy anticancer therapeutics, 211 drug delivery, 268 heterogeneity and adoptability, mitocan therapies, 212 mitochondrial nanotechnology conventional anticancer drugs, 267 multidrug resistance (MDR), 266 mitochondria-specific bioavailability, 269 nanodrug delivery systems DQAsomes, gold nanoparticles, nanolipid vesicles, Carotid body (CB) paragangliomas, 155 Cellular biochemistry/metabolism enzyme activities, m-aconitase role, 85 metabolic pathway, 84 Cephalosporium caerulens, 46 Chemotherapy, Chronic myelogenous leukaemia (CML), 211 Citrate metabolism accelerated glycolysis role, axioms, clinical relevancy and translational application biomarker, 76 malignant prostate loci, premalignant stage, treatment, 76 cytosolic acetyl CoA production citrate export vs. m-aconitase activity, de novo lipid biosynthesis, 67 malignant prostate cells, 68 proliferating tumor cells, 69 normal mammalian cells acetyl CoA, 63 anoxic glycolytic pathway, 62 citrate oxidation, Krebs cycle, 61 normal prostate epithelial cells citrate transporter protein (CTP), mammalian cells, net citrate production, 64 OAA regeneration, 65 rate of synthesis vs. rate of utilization, 65 prostate cancer, 67 role of zinc constitutive levels, electron transport components, 73 iron pools, Zip1 transporter, 72 Citrate production pathway, 66 Citric acid cycle compartmentalization, 132 Clotrimazole, 141 Congenital mitochondrial diseases treatment,

3 Index 283 COX I missense mutations, 7 8 Cytochrome c oxidase (COX) regulation, Cytochrome c oxidase (COX) AMP activated protein kinase (AMPK), 31 cancer genes, 29 frataxin levels, 30 HIF1/, homeostatic regulation, mitochondrial deteriorated, 29 p53 tumor suppressor protein, 29 reactive oxygen species (ROS) generation, 219 Cytochrome c oxidase 2 synthesis (SCO2) regulation, D Dedifferentiated cancer cells, 96 2-Deoxy-D-glucose (2DG), 31 32, Dichloroacetate (DCA) clinical translation in oncology, congenital mitochondrial diseases treatment, preclinical work, D-loop region COX I missense mutations, 7 8 normal vs. tumor cells, 7 DQAsomes, E Electron transport chain (ETC) function, 3 ROS, 9 10 Electron transport chain-targeting drugs, Energy generating metabolic pathways. See Glycolysis Energy metabolism and apoptosis Akt signaling system aerobic glycolysis, Hexokinase II, mtor and FOXO, AMP-activated protein kinase (AMPK) GTPase activating protein (GAP), 112 nutrient scarcity, phosphorylation, 113 glycolytic enzymes, 103 HIF-1 dysregulation hereditary paraganglioma, 118 mitochondrial membrane, oxygen-dependent degradation (ODD), 116 pvhl protein, 116 pyruvate dehydrogenase (PDH), 117 SDH and FH activities, lactate dehydrogenase LDH-A and LDH-B, NADH, 121 tetrameric enzyme, 120 phosphoglucomutase (PGM), 104 pyruvate kinase, role of p53 glycolytic enzymes, hypoxia inducible factor, 116 mitochondrial function, 115 SCO2 levels, 113 TP53-induced glycolysis and apoptosis regulator (TIGAR), Von Hippe Lindau factor (VHL), 105 Warburg concept, 123 Epidermal growth factor (EGF), 43 F Factor B protein, Familial oncocytomas primary and secondary oncocytic carcinoma, sporadic oncocytic cell tumors, Fatty acid synthase (FASN) antineoplastic intervention, cancer cells, mechanisms, Fluoro-deoxy-D-glucose, 26 Fumarate hydratase (FH) catalyzes, inborn deficiency, 154 occurence, 153 urea cycle role, Fumerate, 157

4 284 Index G Glucose oxidation (GO), Glucose transporters (GLUT) glucose uptake, normal cell physiology, 41 Glutaredoxin (Grx) family, 225 Glutathionylation, Glycolysis compartmentalization, direct regulation by p53 phosphoglycerate mutase (PGM), type II hexokinase, genetic control Akt/PBK (protein kinase B), 28 GLUT1, 27 HIF1/, LDHA gene, 27 positron emission tomography (PET), p53 tumor suppressor protein, tumor suppressors and oncogenes, 26 glucose transporters (GLUT), hexokinase II, indirect regulation by p53 LKB1 and AMPK, TP53-induced glycolysis and apoptosis regulator (TIGAR), phosphoglycerate mutase (PGM), product regulation by p53, 144 therapeutic targets, tumor cell metabolism, 80 Gold nanoparticles, GRIM-19 mutations, GTPase activating protein (GAP), 112 H Heat shock proteins (HSPs), 95 Hematological system aging hematopoietic stem cells (HSC), homoplasmy drift cell cycle regulation, mechanisms, mutagenesis, Hematologic disorders acquired idiopathic sideroblastic anemia (AISA), mitochondrialmyopathy, lactic acidosis and sideroblastic anemia (MLASA), myelodysplastic syndromes (MDS), Pearson s syndrome (PS), Hematologic malignancies early detection, leukemia, leukemogenesis, lymphoma, Hereditary leiomyomatosis/renal cell cancer (HLRCC) pathogenesis mechanism, 156 tumorigenesis mechanism, Hexokinase II (HK-II), Hexokinase inhibitors, HIF-1 dysregulation, energy metabolism hereditary paraganglioma, 118 mitochondrial membrane, oxygen-dependent degradation (ODD), 116 pvhl protein, 116 pyruvate dehydrogenase (PDH), 117 SDH and FH activities, Homoplasmy drift cell cycle regulation, mechanisms active selection processes, random processes, Human (degenerative and neoplastic) disorders. See Mitochondrial DNA (MtDNA) Hürthle cell tumors. See Thyroid gland tumors Hypoxia-inducible factor (HIF), 94 hexokinase II (HK-II), lactate dehydrogenase isoform (LDH-M), prolyl hydroxylases (HPHs), 156 pyruvate dehydrogenase (PDH) complex, 215 Hypoxia inducible factor (HIF-1), 116

5 Index 285 I Inherited tumor susceptibility hereditary leiomyomatosis/renal cell cancer (HLRCC) pathogenesis mechanism, 156 tumorigenesis mechanism, Krebs cycle enzymes, paraganglioma (PGL) pathogenesis chronic hypoxic stimulation, 155 SDHD/SDHB gene mutations, succinate accumulation, 156 Insulin-like growth factor-1 (IGF-1), 43 K Keratinocyte growth factor (KGF), 43 Akt-mediated, FASN protein, 46 growth factors, 43 SREBPs, 44 normal cell physiology ATP citrate lyase (ACL), 40 de novo pathway, 40, 42 functions, 39 glucose transporters (GLUT), 41 lipid molecules, lipoprotein lipases (LPL), 40 tumor cell biology, Lipophilic cations, Liposomes. See Nanolipid vesicles LKB1 regulation, 137 Lonidamine, Lymphoma, L Lactate dehydrogenase A (LDHA) gene, 27 Lactate dehydrogenase isoform (LDH-M), Leber s hereditary optic neuropathy (LHON) mutations. See Bone marrow apoptosis Leukemia, Leukemogenesis, pathogenesis, 174 tumor suppressors, 170 Lipogenic switch antineoplastic intervention AMPK activation, 48 cytotoxic effects, 49 FASN inhibition, fatty acid synthesis pathway, 46 malonyl-coa, 48 mevalonate pathway, 49 neu-n transgenic mouse model, 47 therapeutic treatments, cancer cell acetyl-coa, 43 de novo synthesis, 42 FASN levels, mechanism ACC-alpha, M M2-isoform of pyruvate kinase (M2-PK), 104 Mitocans. See also Apoptosis BH3 mimetics, 232 cancer cell apoptosis, 226 class III and IV, drugs for other sites, 237 electron transport chain-targeting drugs, hexokinase inhibitors, lipophilic cations, terminology, 212 types and targets, Mitochondria cancer cells hypoxia-inducible factor (HIF) activation, proton flux regulation, 217 pseudohypoxia, reactive oxygen species (ROS) generation, cancer development, genetic models glucose oxidation (GO), glycolysis, cancer therapy anticancer therapeutics, 211 heterogeneity and adoptability, mitocan therapies, 212

6 286 Index citrate metabolism accelerated glycolysis role, axioms, clinical relevancy and translational application, cytosolic acetyl CoA production, normal mammalian cells, normal prostate epithelial cells, prostate cancer, 67 role of zinc, drug delivery, 268 fetal life mutation, functions, 152 haplotypes, 164 hematological system aging hematopoietic stem cells (HSC), homoplasmy drift, mutagenesis, hematologic disorders acquired idiopathic sideroblastic anemia (AISA), mitochondrialmyopathy, lactic acidosis and sideroblastic anemia (MLASA), myelodysplastic syndromes (MDS), Pearson s syndrome (PS), hematologic findings, 171 hematologic malignancies early detection, leukemia, leukemogenesis, lymphoma, iron accumulation myelodysplastic syndromes, sideroblastic anemia, K + channel axis and apoptosis regulation, leukemogenesis in, 170 nanodrug delivery systems DQAsomes, gold nanoparticles, nanolipid vesicles, nanotechnology in cancer therapy conventional anticancer drugs, 267 multidrug resistance (MDR), 266 oncocytic tumors parathyroid glands, phenomena of, salivary glands, in thyroid, oncocytomas designation, 193 in thyroid, renal oncocytomas mtdna alterations, OXPHOS impairment and D-loop mutations, subcellular drug biodistribution, 269 Mitochondria and cancer biomarkers, 12 chemotherapy, function ETC, 3 fatty acid oxidation, 4 genome mtdna, 4 mtdna vs. nuclear DNA, 5 6 genome changes D-loop region, 6 mtdna, 7 8 normal vs. tumor cells, 7 metabolic differences, 6 nuclear genome changes, 8 photochemotherapy (PCT), 13 ROS role, 9 10 stress signaling glutathionylation, HIF-1/ protein, 11 nitrosylation, 12 peripheral benzodiazepin receptor (PBR), 10 structure, 2 Mitochondrial DNA (MtDNA) mutations, 195 Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) missense mutation, point mutation, 171 Mitochondrial permeability transition pore (MPTP), 227 Mitochondrial respiration and differentiation

7 Index 287 electron respiratory chain, 96 estrogen role, 96 LDH activity, 96 molecular biology, NADPH dehydrogenase, 97 nongenomic effects, 97 pathophysiological processes, thiazolidinediones and fibric acid acetylcysteine (NAC), NADH dehydrogenase dysfunction, peripheral modulation, 98 rhabdomyosarcoma cells, Mitogen activated protein kinases (MAPKs), 95 Molecular genetics and proteomics biochemist approach metabolic pathway, molecular biology, 88 mutations, 89 contemporary application, 87 geneticist approach cellular metabolism, 90 enzyme activities, molecular proteomics, 89 Multidrug resistance (MDR), 266 Myelodysplastic syndromes (MDS) ATP deficiency and chromosomal instability, bone marrow apoptosis, disease characterization, mitochondrial DNA mutations, N NADH:NAD+ ratios. See Akt kinase pathway Nanodrug delivery systems DQAsomes, gold nanoparticles, nanolipid vesicles, Nanolipid vesicles, Nanotechnology, cancer therapy conventional anticancer drugs, 267 multidrug resistance (MDR), 266 Normal cell physiology, lipogenic switch O ATP citrate lyase (ACL), 40 de novo pathway, 40, 42 functions, 39 glucose transporters (GLUT), 41 lipid molecules, lipoprotein lipases (LPL), 40 Oncocytes, 193 Oncocytic tumors parathyroid glands, phenomena of, salivary glands, in thyroid biochemical analyses, chromosomal abnormalities, mtdna common deletion (CD), oncocytic lesions and complex I mutations, Oncocytoma. See also Renal oncocytomas designation, 193 in thyroid, Oxidative phosphorylation (OXPHOS), 151 P Paraganglioma (PGL) chronic hypoxic stimulation, 155 pathogenesis, 158 SDHD/SDHB gene mutations, succinate accumulation, 156 Pearson s syndrome (PS) disease characterization, mitochondrial DNA mutations, 175 Peripheral benzodiazepin receptor (PBR), 10 Peroxisome proliferator-activated receptors (PPARs), 97 Phosphoglycerate mutase (PGM) downregulation, Photochemotherapy (PCT), 13 PI3K Akt pathway, 223 Positron emission tomography (PET), 131 Prolyl hydroxylase enzymes (PHDs), 94 Prolyl hydroxylation, 213 Prostate cancer. See Citrate metabolism

8 288 Index Pseudohypoxia, Pyruvate dehydrogenase (PDH) complex, 215 R Reactive oxygen species (ROS), 9 10 Akt kinase pathway, general model apoptosis Bax protein, caspase activation, generation, 219 PI3K Akt pathway, 223 residual respiratory function, thiol redox system Factor B protein, thioredoxin (TRX), thioredoxin peroxidase II (TPX-II), Refractory anemia with ringed sideroblasts (RARS), Renal oncocytomas mtdna alterations, OXPHOS impairment and D-loop mutations, Ringed sideroblasts, 173 S Salivary gland neoplasm, Sesquiterpene lactones, 237 Sideroblastic anemia, Sterol regulatory element-binding proteins (SREBPs), 44 Subcellular drug biodistribution, 269 Succinate dehydrogenase (SDH), inborn deficiency, 154 structural morphology, 153 Superoxide dismutase (SOD), 9 10 Synthesis of cytochrome c oxidase 2 (SCO2), 113 T Thiol redox system, ROS factor B protein, thioredoxin peroxidase II (TPX-II), Thioredoxin (TRX), Thioredoxin peroxidase II (TPX-II), Thyroid gland tumors biochemical analyses, chromosomal abnormalities, mtdna common deletion (CD), oncocytic lesions and complex I mutations, TP53-induced glycolysis and apoptosis regulator (TIGAR ), 28, Tuberous sclerosis complex (TSC1/TSC2), 112 Tumor cell metabolism axioms, cellular biochemistry, contemporary era, 80 malignant cells parasitic existence defines, in situ environment, metabolic genes concept, metabonomics, 91 mitochondrial enzyme, molecular genetics and proteomics biochemist approach, contemporary application, 87 geneticist approach, Tumor suppressor p53 aerobic respiration proteins regulation cytochrome c oxidase (COX), cytochrome c oxidase 2 synthesis (SCO2), glucose transporters (GLUT), glycolysis and aerobic respiration product regulation, 144 LKB1 and AMPK regulation, phosphoglycerate mutase (PGM) downregulation, signaling cascades, 132

9 Index 289 TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) role, type II hexokinase upregulation human malignancies, mitochondrial localization, Type II hexokinase upregulation human malignancies, mitochondrial localization, V VEGF-receptor-2 (VEGFR-2), 51 Voltage-dependent anion channel (VDAC) protein drug targets, 233 hexokinase II activation, W Warburg effect 2-deoxy-D-glucose (2DG), lonidamine, 32 metabolic characteristics, 23 Warthin s tumor. See Salivary gland neoplasm X XTC.UC1 cell line, 199 Z ZnLigand pool, 72

Metabolism of cardiac muscle. Dr. Mamoun Ahram Cardiovascular system, 2013

Metabolism of cardiac muscle. Dr. Mamoun Ahram Cardiovascular system, 2013 Metabolism of cardiac muscle Dr. Mamoun Ahram Cardiovascular system, 2013 References This lecture Mark s Basic Medical Biochemistry, 4 th ed., p. 890-891 Hand-out Why is this topic important? Heart failure