Inhibition of mitochondrial succinate oxidation--similarities and differences between N-methylated beta-carbolines and MPP+.
N-Methylated beta-carbolinium compounds (N-Me-BCs), including 2-N-methyl and 2,9-N,N-dimethyl analogs, structural analogs of 1-methyl-4-phenylpyridinium (MPP+), may be endogenously bioactivated, MPP(+)-like toxins, capable of inducing parkinsonism. Both MPP+ and selected N-Me-BCs inhibit NADH-linked mitochondrial respiration (Complex I). We now show that both also inhibit succinate-supported (Complex II) respiration, the greatest inhibition (80%) being seen for 2,9-dimethylharmanium. Complex I inhibition occurs at MPP+ concentrations (IC50 = 0.17 mM) about one order of magnitude lower than Complex II inhibition (greater than 1.2 mM). In contrast, Complex I and Complex II inhibition by the N-Me-BCs tested occurred at similar concentrations (I, 0.1 mM; II, 0.25 mM) and concentrations similar to Complex I inhibition by MPP+. 2,9-N,N-Dimethyl-BCs, which are the permanently charged BC analogs of MPP+, show inhibitory characteristics similar to MPP+: slow onset of inhibition, potentiation by TPB, and reversal by DNP. The fact that succinate oxidation cannot bypass the Complex II inhibition by N-Me-BCs could enhance any chronic neurotoxicity of N-Me-BCs.
Fields
J Z
JZ
Department of Pharmacology, University Stritch School of Medicine, Maywood, Illinois 60153.
Albores
R R
RR
Neafsey
E J
EJ
Collins
M A
MA
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D042963:Electron Transport Complex II; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors*; D005260:Female; D007700:Kinetics; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*; D013386:Succinates / Q000378:metabolism*
D002243:Carbolines; D009097:Multienzyme Complexes; D013386:Succinates; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone); D014450:Electron Transport Complex III; D015655:1-Methyl-4-phenylpyridinium