1. 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. 2 PHM142 UNIT 9B Mitochondrial Function and hepatic detoxification of a) monoamines, alcohol, toluene b) heme & bilirubin

3. 3 a)Detoxification of monoamines catalysed by mitochondrial outer membrane MAO R-CHNH 2 O2O2 H2O2H2O2 R-CH=NH NH 3 R-CHO R-COOH  -oxidation CO 2 ATP, HCO 3 - UREA urea cycle MONOAMINE OXIDASE Flavin-containing amine oxidase (imine) inner membrane outer membrane e.g., dopamine norepinephrine tyramine phenethylamine octylamine serotonin aldehyde dehydrogenase NAD + NADH

4. 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). Cheese Tyramine (  g/g) English Stilton1157 Blue998 Mozzarella158 Feta76 Processed cheese slicenil Cheese Tyramine (  g/g) Cheddar cheese, old1530 Beer2-11 Sherry Wine3 Chianti Wine25 Perry, 1996. http://www.vh.org/adult/provider/psychiatry/CPS/19.html

5. 5 b)Detoxification of alcohols by matrix ALDH2 ETHANOL acetaldehyde cytosolic alcohol dehydrogenase NAD + NADH Methyl pyrazole Covalently binds to protein-NH 2 NAD + NADH aldehyde dehydrogenase acetate ATP CoASH acetylCoA CO 2 TCA cycle ANTABUSE (disulfiram) or cyanamide ADHALDHSuscept. to alcoholismAppearance social drinking Chromosome #49, 12, 17 Caucasians99% normal90% normal 10% (  >  ) -- Japanese90% atypicial40% deficient< 10%flushing (ADH) (ALDH)

6. CONHCH 2 COOH Hippuric acid URINE glycine CH 3 CH 2 OHCHO COOH TolueneBenzyl alcohol Benzaldehyde Benzoic acid ADH ALDH1/ ALDH2 Cyt P-450 Teratogen Update: Toluene teratology. 55, 145-51, (1997) Benzoyl-CoA synthetase ATP CoA Benzoyl-CoA N-acyltransferase c) Benzoic acidosis induced by toluene glue sniffing ER CYTOSOL MITOCHONDRIA 5

7. 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 8

9. 9 Heme biosynthesis in bone marrow (hemoglobin) and liver (cytochromes) 1 or lead NH 2

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

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

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

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

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

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

16. 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. 17 *mutated gene in Gilbert’s disease (carried by 15% of population)