Mitochondria, Oxidants, Aging

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monchi
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Mitochondria, Oxidants, Aging
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2010-09-18 17:08:31
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IBHS 2nd exam Dr Richard\'s 2nd lecture
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IBHS Mitochondria, Oxidants, Aging
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  1. Quick Metabolism Summary:
    Glycolysis (in the cytoplasm)
    -Uses Carbs (glucose)
    -No oxygen needed
    - Produces LOW ATP ( only dos remember)
  2. Quick Metabolism Summary: (if your cells need a HIGH metabolic use)
    TCA/ ETC (in Mitochondria)
    -Uses Carbs, Fatty Acids, Amino Acids
    -Requires Oxygen
    -Produces HIGH ATP
  3. When 2 organisms interact or combine to the benefit of each other.
    ----> MAY result in a new "entity"
    SYMBIOSIS
  4. PROKARYOTES:

    ANCIENT ARCHAEA
    • ~ 6,000 genes
    • SPECIALTY- little energy from alot of sources
    • -AN-Aerobic

    • Process
    • Glycolysis (remember AN-aerobic)
    • -Low ATP
  5. Prokaryotes:

    Ancient Bacteria
    • ~ 3,000 genes
    • Speciality- alot of energy from little bit of sources
    • - AEROBIC

    • Process:
    • TCA cycle
    • Oxidative Phosphorylation
    • -HIGH ATP
  6. Define Symbiosis
    • 2 organisms interact or combine to the benefit of each other
    • ---> MAY result in a new "entity"
  7. Ancient Bacteria: aerobic or anaerobic
    Aerobic Hence TCA cycle/ Oxidative Phosphorylation
  8. Ancient Archaea: aerobic or anaerobic
    anaerobic HENCE Glycolysis(low ATP)
  9. Symbiosis:
    Termite is an example of symbiosis… ugly white bug+prokaryote
  10. What does the symbiosis of ancient archaea and anciet bacteria create?
    Ancient Eurkaryota
  11. Ancient Eurkaryota:
    -Genome:~9,000 (from ancient archaea: ~6000genes and ancient bacteria= ~3000)
    -Speciality= Alot of energy from a lot of sources
    ANAEROBIC or AEROBIC
    Process:
    High ATP via- Glycolysis, TCA, and Oxidative Phosphorylation
  12. Ancestor to all modern Eukaryotes including all animal and plant cells
    ANCIENT EUKARYOTA
  13. Evidence of bacterial origin (MITOCHONDRION/ia)
    1. Circular DNA (have their own DNA)
    2. Reproduce by binary fission (like self replication)
    3. Double Membrane (original membrane with a new one wrapped around it)
  14. How many genes in mitochodria?
    37 genes BUT ~1500 genes needed to create mitochondrial proteins (most have relocated to the nucleus)
  15. How do bacteria replicate?
    Binary Fission (this is where Mitochondria get it from... remember symbiosis of ancient bacteria and ancient archaea)
  16. Cells that have the HIGHEST metabolic need require MORE mitochondria
  17. RBC have no mitochondria so how do they meet their metabolic needs?
    Through glycolysis (anaerobic)
  18. How many mitochondria per cell do WBC have?
    ~300 mitochondria (~10% of their cell volume)
  19. How many mitochondria per cell do Liver cells have?
    ~1,000 mitochondria per cell (~20% of their cell volume)
  20. How many mitochondria per cell do Cardiac or Skeletal muscle cells have?
    ~3,000 mitochondria per cell(~40% of their cell volume)
  21. Which type of cells has the MOST mitochondria per cell?
    Egg (~100, 000... replication... creating baby HEY women NEED ALOT)
  22. How many mitochondria per cell do sperm cells have?
    ~100 (insignifcant compare to women's eggs because they only need enough to drive MOBILITY)
  23. When egg and sperm join, all of the mitochondria from the sperm are destroyed via?
    UBIQUITINATION (so only the mitochondria from the egg remains.... QUITTERS!!!!)
  24. Cyanide decreases mitochondrial activity because....
    interferes with protein in Electron Transport chain
  25. Decreased Mitochondrial Activity may be caused by what medications or toxic drugs?
    • Valproic Acid
    • Aspirin
    • Cyanide
    • Statins
  26. Which drugs interfere with proteins in ETC?
    Aspirin, Cyanic and Valproic Acid
  27. STATINS cause decreased Mitochondrial Activity
    -It can interfere with mitochondria
    -Most common adverse event is muscle pain or fatigue
  28. What are the 3 main causes of decreased mitochondrial activity?
    • 1. Medication/ Toxic Drugs
    • 2. Infections
    • 3. Congenital disorders
  29. Mitochondrial Disorders:
    Symptoms
    problems with HEART, KIDNEYS, BRAIN and Active Skeletal Muscle. (ALL have HIGH ATP demands)
  30. Mitochondrial Disorders:
    Diagnosis made ... if the following are found:
    mtDNA mutations
    Increased lactic acid
    Increased proliferation of mitochondria
  31. If mitochondrial is not working correctly why would it proliferate?
    The cell is conpensating and making more because the ones there are only doing half their jobs
  32. Mitochondrial Disorders:
    Treatments:
    • Heart- anti-arrythmic meds
    • Brain- anti seizure meds
    • Skeletal muscles- Physical Therapy
    • To potentially reduce potential oxidants--- vitamins, coenzymes, and antioxidants
  33. What is the MAJOR role of oxygen during the Electron Transport Chain?
    final electron acceptor.
  34. Electron Transport Chain: Overview
    THE PLAYERS;
    •NADH & FADH2 from Glycolysis, TCA prep & TCA
    •Proteins of the ETC: Coenzymes & cytochromes transfer electrons through a series of oxidation-reduction reactions. Some can act as H+ pumps
    • Oxygen: final electron acceptor
  35. As e- moves through ETC it may prematurely combine with O2... what is made?
    SUPEROXIDE (e- + O2 --> O2- )
  36. SuperOxide is a/an:
    -Oxidant
    -Free Radical
    -Reactive Oxygen Species (ROS)
  37. Oxidant
    a molecule that accepts an electron
  38. Any molecule with a single unpaired electron
    Free Radical
  39. Wants to react with other molecules
    Reactive Oxygen Species (ROS)
  40. A molecule that accepts an electron
    Oxidant
  41. Free Radical
    Any molecule with a single unpaired electron
  42. Reactive Oxygen Species (ROS)
    wants to react with other molecules
  43. SUPEROXIDE : SO = O2-
  44. Generation of SO is a normal occurrence in all cells

    –95% of e- combine with H+ and O2 ---> H2O

    –5% of e- combine with O2 ---> O2- = SO
  45. What percent of electrons combine with oxygen prematurely to create SUPEROXIDE?
    5%
  46. Cells have ___________ mechanisms to elimante SO
    antioxidant
  47. Superoxide:
    Bad news
    - If too many oxidants it can overwhelm the antioxidants
    - If too few antioxidant it can't eliminate SO fast enough
  48. May 2008
    (10 year study results announced at Pediatric Academic Societies conference meeting)
    • 500 (6month old babies)
    • Group A: given lower iron formula for 1 yr
    • Group B: given higher iron formula for 1 yr

    • 10 years later:
    • Group A:
    • Group B: (the ones with the HIGHER iron formula)
    • -lower IQ
    • -lower spatial memory
    • -lower visual perception
    • -lower motor coordination
  49. ´╗┐SO (O2-) catalyzed by SuperOxide Dismutase (SOD) to Hydrogen Peroxide (H2O2)
    • Bad: H2O2 is still an oxidant
    • Good: H2O2 not as dangerous as SO
  50. In the prescence of Fe( or Cu) Hydrogen Peroxide is catalyzed to Hydroxyl Radical (OH)
    • Bad: OH is still an oxidant
    • SUPERbad: OH much worse than SO
  51. Placed the following in order of most dangerous (1) to least dangerous (3):
    Superoxide, Hydrogen peroxide, Hydrogen Radical
    • 1. Hydrogen Radical (OH)
    • 2. SO (O2-)
    • 3. Hydrogen Peroxide (H2O2)
  52. What enzyme is catalyzes Superoxide to Hydrogen Peroxide?
    SuperOxide Dismutase (SOD)
  53. O2- and OH are technically free radicals, and all 3 are ROS or oxidants
  54. Which of the following is not a free radical?
    A. OH
    B. O2-
    C. H2O2
    C. H2O2
    (this multiple choice question has been scrambled)
  55. Hydroxyl radical attacks organic molecules, compromises bonds, damages structure/function relationships
    it affects every molecule inside a cell (DNA/RNA, Protein, Lipid and Carbohydrate OXIDATION)
  56. Hydroxyl Radical: Molecular Damage:

    DNA/RNA
    • Genetic Damage/Mutations
    • - transcription/translation errors and inhibition
    • - shortening of telomeres
  57. Hydroxyl Radical: Molecular Damage:

    Proteins
    • Denaturation: protein unfolding or misfolding
    • -modified ion transport/enzyme activity
    • -increased calcium influx
  58. Hydroxyl Radical: Molecular Damage:

    Carbohydrates
    • Glycation: non-enzymatic binding to proteins
    • - impairs function of proteins
  59. Hydroxyl Radical: Molecular Damage:

    Lipids
    • Lipid peroxidation: chain reaction of bond breaks
    • - altered membrane fluidity and permeability
    • - altered membrane-bound enzymes (directly or indirectly)
  60. molecular change ----> cellular change
  61. July 2008
    (Journal of The National Cancer Institute)
    • 1,200 old men
    • –Group A: no blood removal
    • –Group B: blood removed every six months

    • 5 years later
    • –Group A: had no blood removal
    • –Group B: had blood removal every six months
    • Half as many cancers
    • Lower iron levels correlated with lower cancer rates
  62. Biggest theory of why women live longer?
    Menstration- Getting rid of iron less likely hydroxy peroxide will be driven to hydroxy radical
  63. Journal of The NATIONAL CANCER institute (July 2008)

    Replicated menstration (men giving blood every 6 months... although women do it monthly)
  64. Enzyme that generates Nitric Oxide (N.O.)
    Nitric Oxide Synthase (NOS)
  65. Other Sources of Oxidants:
    Nitric Oxide Synthase (NOS)
    • An Enzyme that generates nitric oxide (N.O.)
    • -NO is a free radical
    • -In large amounts it is BAD
    • ---- Combine with oxygen to form Reactive Nitrogen Oxygen Species
    • ---- NO + O2 --> RNOS --> damages nearby molecules
  66. What enzyme combines with SuperOxide to make Nitric Oxide and then makes Reactive Nitrogen Oxygen Species?
    Nitric Oxide Synthase
  67. Other Sources of Oxidants:

    Ionizing Radiation
    • Can create hydroxyl radical via:
    • --Cosmic rays, radioactivity , X-rays and UV
  68. UV can directly or indirectly damage cells....

    Directly- skin (skin cancer... you know this MAN)
    INDIRECTLY: A high energy radiation hits the water molecule which splits it to a hydrogen ion and a hydroxy radical SUPERBAD!!!!
  69. Again: IONIZING RADIATION

    H2O -----ionizing radiation----> OH (hydroxyl radical SUPERBAD) + H+ (Hydrogen atom)
    INDIRECT damage of UV to DNA
  70. Overall oxidants can do Molecular Damage ---> Cellular Damage ---> Organ Damage
  71. Some factors of Aging:
    Telomeres Shortening: Chromosomes lose telomeres over time
    Choronlogical Age: Risk factors increase over time
    Glycation: Glucose sugar binds to and inhibits DNA, proteins and lipids (DUE TO OXIDANTS)
    Oxidative Stress: Oxidants damage DNA, proteins and lipids
  72. Some conditions that may entail free-radical injury
    • Atherogenesis, Emphysema; bronchitis, Parkinson disease
    • Duchenne muscular dystrophy, Cervical Cancer, Alcoholic liver disease
    • Diabetes, Acute renal Failure, Down Syndrome, Retrolental fibroplasia
    • Cerbrovascular disorders, Ischemia; reperfusion injury
  73. DEFENSES

    1. Antioxidant Enzymes
    2. Iron sequestration
    3. Free Radical Scavengers
  74. Defense Type #1: ANTIOXIDANT ENZYMES:

    Name the 3 enzymes...
    • -SOD
    • -Glutathione Peroxidase
    • -Catalase
  75. MOST Hydrogen Peroxide never gets converted to Hydroxyl Radical because of _______________
    ANTIoxidant enzymes
  76. SELENIUM- forms active center of Glutathione Peroxidase (GP), why is GP imporant?
    Glutathione Peroxidase catalyzes Hydrogen Peroxide into 2 water molecules
  77. Defense Type #1: antioxidant enzymes
    SuperOxide Dismutase (SOD)
    - mice without SOD die of OXIDATIVE damage within 2 weeks
  78. Defense Type #1: antioxidant enzymes
    Glutathione Peroxidase (GP)
    -Catalyzes : Glutathione (GSH) + H2O2----> H2O + H2O
    -Selenium: forms active center of GP enzyme
  79. What antioxidant enzyme catalyzes hydrogen peroxide into 2 water molecules?
    Glutathione Peroxidase
  80. Defense Type #1: antioxidant enzymes
    Catalase
    Catalyzes: H2O2---> H2O + O2
  81. What catalyzes hydrogen peroxide into 1 water molecule and oxygen?
    Catalase
  82. Origin of Gray Hair: As we get older we produce less _______ and so more H2O2 builds up and damages the melanin that pigments the hair
    catalase
  83. What builds up because of less catalase production which in turn causes gray hair?
    Hydrogen Peroxide
  84. Protein without iron bound
    Apoferritin
  85. Protein with iron bound
    Ferritin
  86. Aggretates of ferritin
    Hemosiderin
  87. Defense Type #2: Iron Sequestration

    Chelation of iron by proteins.... what proteins?
    • Apoferritin
    • Ferritin
    • Hemosiderin
  88. Ferritin
    • Protein with iron bound
    • Each ferritin complex can store about 4500 iron (Fe3+) ions
  89. Chelation means what?
    BINDING UP ( iron is being bounded by protein to avoid Hydrogen from binding to prevent HYDROXYL RADICAL (superbad)
  90. Defense Type #3: Free Radical Scavengers

    Scavengers passively absorb the damage
    • Vitamin A (fat soluble in cell membrane)
    • Vitamin C (water soluble in cytoplasm)
    • Vitamin E (fat soluble)
  91. Vitamin found in sweet potatoes, carrots, broccoli, spinach
    Vitamin A
  92. Vitamin found in citrus, pepper, brocolli, cabbage
    Vitamin C
  93. Protects against lipid peroxidation, found in margarine, vegetable oil, wheat germ, green leafy vegetables?
    Vitamin E
  94. Beta Carotene
    Vitamin A (found in CARROTS)
  95. Ascorbic Acid
    Vitamin C
  96. Alpha Tocopherol
    Vitamin E
  97. Bolstering Antioxidants:
    MOST IMPORTANT study that sparked the antioxidant phenom***
    • 1993, Cynthia Kenyon
    • –C. elegans (worm) usually live 24 days
    • –Inserted “antioxidant” genes
    • –“Guess how old my worm is”
    • –Lived for 144 days
  98. Bolstering Antioxidants

    2005, Science
    • Inserted gene for catalase into mice
    • they lived 15% longer
  99. Antioxidant Supplements:

    2007, Annals of Internal Medicine
    • Healthy adults : 8yrs of selenium or placebo
    • Selenium increase risk of diabetes
  100. Antioxidant Supplements:

    2007, Archives of Internal Medicine
    • 40+ year old; 9yrs of vitamin C, E, beta carotene, or placebo
    • No reduction of cariovascular problems or death
  101. Antioxidant Supplements:

    2007, JAMA (meta-analysis of 47 studies_
    • NO reduction of mortality with vitamin C, selenium
    • Increased mortality with: Vitamin A and Vitamin E
  102. Antioxidant Supplements:

    2008, Cochrane Review (meta-analysis of 67 studies)
    • No reduction of mortality with : vitamin C, selenium
    • Increased mortality with: Vitamin A and Vitamin E
  103. Cancer and Antioxidants:

    2009, Journal of Clinical Oncology
    • Prostate Cancer patients + Antioxidants (selenium)
    • -increased cancer rates
  104. Cancer and Antioxidants:

    2009, Nature
    • In Vitro Breast Cancer cell + Antioxidants
    • - Cancer cells had less oxidants and lived LONGER
  105. Cancer and Antioxidants:

    2010, American Society of Clinical Oncology
    • Lung Cancer patients + Selenium
    • -No benefit, some detriment
  106. OXIDANTS not always bad Can be USEFUL:

    Nitric Acid
    • Cell signaling
    • Neurotransmitter
    • Vasodilation
  107. OXIDANTS not always bad Can be USEFUL:

    Peroxisomes and lysosomes
    Degradation of endogenous biomolecules
  108. OXIDANTS not always bad Can be USEFUL:

    Apoptosis (programmed cell death)
    • Oxidant damage important for getting rid of unwanted cells
    • -infected cells, cancer cells, damaged cells
  109. OXIDANTS not always bad Can be USEFUL:

    Defense
    • Many cells use oxidants against microorganisms
    • -Especially neutrophils and macrophages (WBCs)
  110. How do you increase longevity in healthy individuals?
    • Choose your parents
    • Less Calories= Less oxidants
    • More exercise= More antioxidants
    • Less Calories + More Exercise
  111. How do you increase longevity in healthy individuals?

    Choose your parents
    • Genetics is best predictor of longevity
    • Specific genes correlated with 3 times better chance of living to be 95
  112. How do you increase longevity in healthy individuals?

    Less Calories= Less Oxidants
    • 40% decrease of calories increasess lifespan of most animals
    • Big decrease in oxidants, small increase in antioxidant enzymes
  113. How do you increase longevity in healthy individuals?

    More Exercise= More antioxidants
    • Big, Short bursts of oxidants result in big sustained increase in antoxidant enzyme levels
    • Exercise can counter the natural decrease in antioxidant enzymes with aging
  114. How do you increase longevity in healthy individuals?

    Less Calories + More Exercise
    Benefits of 40% caloric restriction can be achieved with 8% caloric reduction and regular exercise

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