Tyramine and monoamine oxidase inhibitors as modulators of the mitochondrial membrane permeability transition.
Incubation of rat liver mitochondria with 100-500 mM tyramine, a substrate for monoamine oxidases A and B (MAOs), in the presence of 30 mM Ca2+ induces matrix swelling, accompanied by collapse of membrane potential, efflux of endogenous Mg2+ and accumulated Ca2+ and oxidation of endogenous pyridine nucleotides. These effects are completely abolished in the presence of cyclosporin A, ADP, dithioerythritol and N-ethylmaleimide, thus confirming the induction of the mitochondrial membrane permeability transition (MPT). The observed partial protective effect exerted by catalase indicates the involvement of both MAO-derived hydrogen peroxide and aldehyde. Higher concentrations of tyramine (1-2 mM) are less effective or even completely ineffective. At these high concentrations tyramine has an inhibitory effect when the MPT is induced by 100 mM Ca2+. The MAO inhibitors clorgyline (50 mM) and pargyline (500 mM) completely protect against MPT induction by 100 mM tyramine but also inhibit the phenomenon, although with different efficacy, when it is induced by 100 mM Ca2+ in the absence of tyramine. Taken together, our data suggest that tyramine, clorgyline and pargyline act as modulators of the MPT either through a direct inducing/protective effect or by controlling hydrogen peroxide and aldehyde generation.
Marcocci
L
L
Department of Biochemical Sciences and CNR Center of Molecular Biology, University of Rome La Sapienza, Rome, Italy.
De Marchi
U
U
Salvi
M
M
Milella
Z G
ZG
Nocera
S
S
Agostinelli
E
E
Mondovi
B
B
Toninello
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003010:Clorgyline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D008274:Magnesium / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects* / Q000502:physiology; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010293:Pargyline / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011920:Rats, Inbred WF; D012016:Reference Values; D014439:Tyramine / Q000494:pharmacology*
D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008996:Monoamine Oxidase Inhibitors; D010293:Pargyline; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase; D008274:Magnesium; D003010:Clorgyline; D002118:Calcium; D014439:Tyramine