ATP DEPLETION & HYPOXIA

Transcription

1 SCBM344 Cellular and Molecular Pathology 2(2-0-4) MECHANISMS OF CELL INJURY: ATP DEPLETION & HYPOXIA PORNTHIP CHAICHOMPOO

2 OBJECTIVES Describe the cellular pathogenesis of cell injury that affect to ATP depletion and hypoxia Describe the mechanisms of ATP synthesis, oxygen sensing and metabolic homeostasis Describe the effect of hypoxia on cellular response and induced disease progression

3 CAUSES OF CELL INJURY 1. Oxygen deprivation: Hypoxia, Ischemia 2. Chemical agents: Ethanol, Air pollutants, etc. 3. Infectious agents: viral, bacterial, fugal pathogens 4. Immunologic reactions: Inflammation, Hypersensitivity 5. Genetic factors: Down syndrome, SCD, etc. 6. Nutritional imbalances: Vitamin-deficient dis., DM, etc. 7. Physical agents: Trauma, Radiation, etc. 8. Aging: Cellular senescence

4 WHAT ARE THE CAUSE OF ISCHEMIA? Occlusion: Thromboembolism Trauma: Injury of carotid artery or aorta Other: Atherosclerosis Hypoglycemia Hypotension Anemia: Sickle cell disease Thalassemia etc. wikipedia

5 WHAT ARE THE CAUSE OF HYPOXIA AND HYPOXEMIA? Ischemia Severe asthma attach Lung diseases such as chronic obstructive pulmonary disease (COPD), emphysema, bronchitis, pneumonia, and pulmonary edema Anemia Cyanide poisoning etc.

6 2004 Georg Thieme Verlag. Riede U., Werner M. Thieme medical publishers.2004.

7 OVERVIEWS Ischemia Hypoxia ATP depletion Kumar et al: Robbins & Cotran Pathologic Basic of Disease, 9 th ed. Copyright 2013 by Saunders, an imprint of Elsevier, Inc., All rights reserved.

8 ATP DEPLETION ATP depletion and decreased ATP synthesis are common with both hypoxic and toxic (or chemical) injury. Na +, K + -ATPase pump activity is reduced. Cellular energy metabolism is changed. Failure of Ca 2+ pump. Reduced protein synthesis.

9 MECHANISMS OF CELL INJURY ATP DEPLETION Kumar et al: Robbins & Cotran Pathologic Basic of Disease, 9 th ed. Copyright 2013 by Saunders, an imprint of Elsevier, Inc., All rights reserved.

10 WHAT IS ATP?

11 ATP ATP is essential for every cellular process : Maintenance of cell osmolarity Transport processes Protein synthesis Therefore, loss of ATP results in rapid shutdown of most critical homeostatic pathways

12 Oxygen Energy System Anaerobic Glycolysis Glucose + 2ADP è 2Lactate + 2ATP Glycogen + 3ADP è 2Lactate + 3ATP Aerobic Oxidative Phosphorylation Glucose + 6O 2 +36ADP è 6CO 2 + 6H 2 O +36ATP Adenosine triphosphate David L. Gee,

13 Glycolysis Hexokinase Glucose + 2ADP è 2Lactate + 2ATP Phosphohexose isomerase Phosphofructokinase-1 (rate limiting step) Aldolase Glyceraldehyde 3-phosphate dehydrogenase Phosphoglycerate kinase Phosphoglycerate mutase Enolase Pyruvate kinase LDHA Lactate dyhydrogenase A LDHA LDHA

14 Glycogen breakdown is catalyzed by glycogen phosphorylase Pi Nonreducing end Glycogen n-1 Biochemistry, 7 th W.H.Freeman and Company

15 During extended exercise Glycogen stores become depleted, muscle cells rely more on glucose uptake from the blood, and on fatty acid catabolism as a source of ATP. Fructose-6-phosphate GLYCOLYSIS PATHWAY Fructose 1,6-bisphosphate Phosphofructokinase ñ AMP + + ñ Anaerobic glycolysis GLYCOGEN PATHWAY Phosphorylase Glycogen chain (glucose) n Shorted Glycogen chain (glucose) n-1 Depletion of glycogen stores ñ Lactic acid & [Pi] ê Intracellular ph IMPAIRED CELL PROLIFERATION & ENZYME ACTIVITY

16 Electron transport & oxidative phosphorylation Glucose + 6O 2 +36ADP è 6CO 2 + 6H 2 O +36ATP PDH PDH; Pyruvate dehydrogenase

17 OXYGEN SENSING & METABOLIC HOMEOSTASIS

18 OXYGEN CONCENTRATION (21% O 2 ) (1-2% O 2 ) (0% O 2 ) Poyton RO, et al. Trends Endocrinol Metab Sep;20(7):

19 ROS & RNOS GENERATE IN DURING HYPOXIA ROS Free radical RNOS Free radical Strong oxidizing agent Poyton RO, et al. Trends Endocrinol Metab Sep;20(7):

20 MITOCHONDRIA RESPONSE TO HYPOXIA Pulmonary Artery Smooth Muscle Cells (PASMC) Increased vasoconstriction McElroy GS & Chandel NS. Exp Cell Res Jul 15;356(2):

21 MITOCHONDRIA RESPONSE TO HYPOXIA Glomus cells (type I), chemoreceptor, in the carotid body McElroy GS & Chandel NS. Exp Cell Res Jul 15;356(2):

22 MITOCHONDRIA RESPONSE TO HYPOXIA McElroy GS & Chandel NS. Exp Cell Res Jul 15;356(2):

23 WHAT IS HIF?

24 OXYGEN BALANCE Pugh CW & Ratcliffe PJ. Exp Cell Res Jul 15;356(2):

25 HIF : HYPOXIA-INDUCIBLE FACTOR Normoxia Hydroxylation Ubiquitination Proteolysis Protein degradation FIH-1; factor-inhibiting HIF-1, PHD; prolyl-4-hydroxylase, VHL; von Hippel-Lindau Koyasu S, et al.cancer Sci [Epub ahead of print]

26 Normoxia Hypoxia P; Proline N; Asparagine Bell EL, et al. Mitochondrion Oct;5(5):

27 Normoxia (21%O 2 ) Bell EL, et al. Mitochondrion Oct;5(5):

28 WHAT IS FUNCTION OF HIF?

29 Transporter protein Palmer BF & Clegg DJ. Mol Cell Endocrinol Nov;397(1-2):51-8.

30 Hypoxia: HIF-1a Gluconeogenesis Minimize accumulation of lactate Increased cellular production of glucose Blocked under Hypoxia Palmer BF & Clegg DJ. Mol Cell Endocrinol Nov;397(1-2):51-8.

31 Hypoxia Increased HIF-1a in the intra cellular HIF-1a Increased Glycolysis via increased PDK-1 and LDHA Increased Glucose level via Gluconeogenesis Increased lactate pump out from cells and uptake into hepatocytes Decreased acidosis from lactic acid via Gluconeogenesis

32 HIF AND IMMUNITY Palazon A, et al. Immunity Oct 16;41(4):

33 HIF AND IMMUNITY Palazon A, et al. Immunity Oct 16;41(4):

34 HIF AND IMMUNITY Palazon A, et al. Immunity Oct 16;41(4):

35 Palazon A, et al. Immunity Oct 16;41(4):

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37 HYPOXIA INDUCED DISEASE PROGRESSION

38 HYPOXIA AND PATHOLOGY Cellular levels Increased HIF-1a (Balance) ATP depletion / Decreased ATP demand (Balance) Mitochondrial damage Excessive load of ROS generation Oxidative stress Lipid peroxidation

39 HYPOXIA AND PATHOLOGY Disease progression Immune response: Phagocytosis and Inflammation Atherosclerosis: modified lipoproteins recruit monocytes and T cells into the intima lead to thrombus formation Anemia: increased erythropoiesis Cancer: increased angiogenesis

40 HYPOXIA AND PATHOLOGY Wheaton WW & Chandel NS. Am J Physiol Cell Physiol Mar;300(3):C

41 HYPOXIA AND PATHOLOGY AMPK; AMP-activated protein kinase, mtorc1; mammalian target of rapamycin, PERK; pancreatic eif2 kinase Wheaton WW & Chandel NS. Am J Physiol Cell Physiol Mar;300(3):C

42 HYPOXIA & LIPID PEROXIDATION Behn C, et al. Respir Physiol Neurobiol Sep 30;158(2-3):

43 HYPOXIA & LIPID PEROXIDATION PUFA; Polyunsaturated fatty acids Behn C, et al. Respir Physiol Neurobiol Sep 30;158(2-3):

44 HYPOXIA & IMMUNITY Konisti S, et al. Nat Rev Rheumatol Jan 31;8(3):

45 HYPOXIA & INFECTION NizetV & Johnson RS. Nat Rev Immunol Sep;9(9):

46 The role of hypoxia-inducible factor 1 in atherosclerosis Gao L, et al. J Clin Pathol Oct;65(10):872-6.

47 HYPOXIA & ATHEROSCLEROSIS Increases the accumulation of triglyceride-containing lipid droplets in human macrophages Oil Red O Hultén LM & Levin M. Curr Opin Lipidol Oct;20(5):

48 HYPOXIA & MACROPHAGES IN ATHEROSCLEROSIS Lipid-loaded macrophages Increased NF-kB transcription factor levels Increased production of IL-8/CXCL8, CXCL10 and CCL2

49 Foam cell formation Moore KJ&Tabas I.Cell.2011;145:

50 Hultén LM & Levin M. Curr Opin Lipidol Oct;20(5):

51 Nascent HDL Foam cell McLaren JE. Et al. Progress in Lipid Research.2011;50:

52 HYPOXIA INDUCED EPO PRODUCTION McElroy GS & Chandel NS. Exp Cell Res Jul 15;356(2):

53 ERYTHROPOIESIS Erythropoietin (Epo) is produced in the kidney to mediate expansion of the erythroid progenitors in the bone marrow Parathyroid hormone (PTH) is released by the parathyroid glands. PTH Skeletal homeostasis Walkley CR. Int J Hematol (2011) 93:10 13

54 HYPOXIA INDUCED ERYTHROID DIFFERENTIATION IN ANEMIA

55 HYPOXIA INDUCED K562 CELL DIFFERENTIATION Sarakul O, et al. Blood Cells Mol Dis Aug;51(2):

56 HYPOXIA INDUCED HUMAN ERYTHROID PRECURSOR CELL DIFFERENTIATION Sarakul O, et al. Blood Cells Mol Dis Aug;51(2):

57 Wheaton WW & Chandel NS. Am J Physiol Cell Physiol Mar;300(3):C

58 Bavelloni A, et al. Anticancer Res Dec;37(12):

59 MIRNA BIOLOGY Cortez MA, et al. Nat Rev Clin Oncol Jun 7;8(8):

60 Hypoxia induced upregulation of mir-210 expression during erythroid differentiation Sarakul O, et al. Blood Cells Mol Dis Aug;51(2):

61 Sarakul O, et al. Blood Cells Mol Dis Aug;51(2):

62 HYPOXIA AND CANCER

63 Noman MZ, et al. Am J Physiol Cell Physiol Nov 1;309(9):C

64 Labiano S, et al. Semin Oncol Jun;42(3):

65 Noman MZ, et al. Am J Physiol Cell Physiol Nov 1;309(9):C

66 Loizzi V, et al. Int J Mol Sci Sep 14;18(9). pii: E1967.

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