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PHM142 UNIT 9A Mitochondrial Diseases and the Brain Instructions and materials:

PHM142 UNIT 9A Mitochondrial Diseases and the Brain Instructions and materials: Read ONLY sections in paper by Chaturvedi and Beal, 2013 (included in lecture material) highlighted in yellow , plus Figures 1 and 3 and Table 1 in this paper. Be prepared to discuss these topics in class.

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PHM142 UNIT 9A Mitochondrial Diseases and the Brain Instructions and materials:

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  1. PHM142 UNIT 9A Mitochondrial Diseases and the Brain Instructions and materials: Read ONLY sections in paper by Chaturvedi and Beal, 2013 (included in lecture material) highlighted in yellow, plus Figures 1 and 3 and Table 1 in this paper. Be prepared to discuss these topics in class.

  2. PHM142 UNIT 9B Mitochondrial Function and hepatic detoxification of a) monoamines, alcohol, toluene b) heme & bilirubin

  3. Detoxification of monoamines catalysed by mitochondrial outer membrane MAO e.g., dopamine norepinephrine tyramine phenethylamine octylamine serotonin outer membrane MONOAMINE OXIDASE Flavin-containing amine oxidase R-CHNH2 inner membrane R-CH=NH (imine) O2 NH3 H2O2 R-CHO NAD+ ATP, HCO3- aldehyde dehydrogenase urea cycle UREA NADH R-COOH b-oxidation CO2 Mitochondrion

  4. Amine specificity for the two isoforms (A & B) in humans MAO A preferentially metabolizes serotonin. MAO B preferentially metabolizes phenethylamine, dopamine. MAO inhibitor + dietary amines or proprietary drugs MAOB inhibitor deprenyl (selegiline) similar to phenethylamine and increases brain dopamine levels. This is used to treat Parkinson’s disease. But “Hypertensive crisis” is a hyperadrenergic state induced by MAO inhibitors + pressor amines (e.g., tyramine in cheese,beer,wine or soya sauce) or proprietary drugs (e.g., L-DOPA, ephedrine, etc). Perry, 1996. http://www.vh.org/adult/provider/psychiatry/CPS/19.html

  5. Detoxification of alcohols by matrix ALDH2 Covalently binds to protein-NH2 (ADH) cytosolic alcohol dehydrogenase acetaldehyde ETHANOL ANTABUSE (disulfiram) or cyanamide NADH NAD+ Methyl pyrazole NAD+ aldehyde dehydrogenase CO2 NADH (ALDH) TCA cycle ATP acetate acetylCoA CoASH

  6. COOH URINE CONHCH2COOH Hippuric acid c) Benzoic acidosis induced by toluene glue sniffing Benzaldehyde Toluene Benzylalcohol ADH Cyt P-450 CH3 CH2OH CHO CYTOSOL ER ALDH1/ ALDH2 MITOCHONDRIA Benzoic acid Benzoyl-CoA synthetase ATP CoA N-acyltransferase Benzoyl-CoA glycine 5 Teratogen Update: Toluene teratology. 55, 145-51, (1997)

  7. Cytochrome Heme Synthesis - Overall picture

  8. Heme synthesis • Heme required for synthesis of mitochondrial cytochromes and endoplasmic reticular P450s. • Heme required for bone marrow synthesis of hemoglobin and muscle myoglobin • STEP 1 for heme synthesis is the synthesis of aminolevulinic acid (ALA) from succinyl CoA of the citric acid cycle and glycine

  9. Heme biosynthesis in bone marrow (hemoglobin) and liver (cytochromes) NH2 or lead 1

  10. Erythropoietin synthesised by kidney induces hemoglobin synthesis in bone marrow (replaces blood transfusion!)

  11. Heme Biosynthesis - STEP 2 in the cytosol (4 enzymes 2-5) 1

  12. Heme Biosynthesis - STEP 3 - mitochondrial final steps (3 enzymes)

  13. OXIDATIVE DEGRADATION OF HEME TO BILIRUBIN (a brain neurotoxin in babies)

  14. Detoxification function of the liver a) heme toxin oxidation to bilirubin b) detoxification of bilirubin by glucuronidation or albumin albumin LIVER CO phagosome Heme oxygenase

  15. Degradation of heme STAGE 1 Hemoglobin of old erythrocyte trapped in spleen

  16. STAGE II - ligandin in hepatocyte surface membrane traps bilirubin from plasma and helps transport it into the liver where it is glucuronidated Albumin - bilirubin (a GSH transferase)

  17. *mutated gene in Gilbert’s disease (carried by 15% of population)

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