Monoamine oxidase and mitochondrial respiration.
Mitochondrial defects encompassing complexes I-IV of the electron transport chain characterize a relatively large number of neurodegenerative diseases. The relationships between mitochondrial lesions and recently described genetic alterations have not yet been defined. We describe a general mechanism whereby the enzymatic metabolism of neurotransmitters by monoamine oxidase (MAO) damages mitochondria, altering their protein thiol status and suppressing respiration. In these experiments, incubation of rat brain mitochondria with tyramine (a mixed MAO-A/MAO-B substrate) for 15 min at 27 degrees C suppressed state 3 respiration by 32.8% and state 5 respiration by 40.1%. These changes were accompanied by a 10-fold rise in protein-glutathione mixed disulfides. Direct comparison of effects on respiration and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] dye reduction during electron flow gave similar results. It is suggested that certain mitochondrial lesions may derive from the natural turnover of monoamine neurotransmitters in susceptible individuals.
Cohen
G
G
Department of Neurology and Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Kesler
N
N
D000818:Animals; D004220:Disulfides / Q000378:metabolism; D004579:Electron Transport / Q000235:genetics; D042967:Electron Transport Complex I; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D008995:Monoamine Oxidase / Q000502:physiology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010300:Parkinson Disease / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014439:Tyramine / Q000378:metabolism / Q000494:pharmacology
D004220:Disulfides; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D013438:Sulfhydryl Compounds; D019289:Pyruvic Acid; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D005978:Glutathione; D014439:Tyramine