Related Experiment Video
Updated: Sep 30, 2026
Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
Published on: September 28, 2019
Tyramine and monoamine oxidase inhibitors as modulators of the mitochondrial membrane permeability transition
L Marcocci1, U De Marchi, M Salvi
1Department of Biochemical Sciences and CNR Center of Molecular Biology, University of Rome La Sapienza, Rome, Italy.
Abstract:
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.
Insights
Tyramine triggers mitochondrial permeability transition (MPT) in rat liver mitochondria by generating hydrogen peroxide and aldehyde. MAO inhibitors also modulate MPT, suggesting complex interactions.
Area of Science:
- Mitochondrial Physiology
- Biochemistry
- Enzymology
Background:
- Monoamine oxidases (MAOs) A and B metabolize substrates like tyramine.
- Mitochondrial membrane permeability transition (MPT) is a critical event in cell death.
- Calcium ions (Ca2+) and reactive oxygen species can induce MPT.
Purpose of the Study:
- To investigate the role of tyramine and its metabolites in inducing MPT in rat liver mitochondria.
- To explore the involvement of MAO activity and its products in MPT.
- To examine the modulatory effects of MAO inhibitors on MPT.
Main Methods:
- Incubation of isolated rat liver mitochondria with varying concentrations of tyramine.
- Measurement of mitochondrial swelling, membrane potential, ion efflux (Mg2+, Ca2+), and pyridine nucleotide oxidation.
- Assessment of the effects of cyclosporin A, ADP, dithioerythritol, N-ethylmaleimide, catalase, and MAO inhibitors (clorgyline, pargyline).
Main Results:
- Tyramine (100-500 mM) with Ca2+ induced MPT, evidenced by swelling, membrane potential collapse, ion efflux, and nucleotide oxidation.
- These tyramine-induced effects were abolished by MPT inhibitors and partially reduced by catalase, indicating roles for hydrogen peroxide and aldehyde.
- Higher tyramine concentrations (1-2 mM) were ineffective or inhibitory, while MAO inhibitors protected against tyramine-induced MPT but also inhibited Ca2+-induced MPT.
Conclusions:
- Tyramine can induce MPT in mitochondria, likely through MAO-generated hydrogen peroxide and aldehyde.
- MAO inhibitors (clorgyline, pargyline) modulate MPT, suggesting they act as direct effectors or influence metabolite generation.
- Tyramine, clorgyline, and pargyline are identified as modulators of mitochondrial membrane permeability transition.
Related Concept Videos
01:23Antidepressant Drugs: MAOIs and Other Agents
01:29Drugs Affecting Neurotransmitter Synthesis
01:21Drugs Affecting Neurotransmitter Release or Uptake
01:25Adrenergic Agonists: Indirect-Acting Agents
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral bioavailability, and...
01:19Translocation of Proteins into the Mitochondria
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
01:26Neurochemical Transmission: Sites of Drug Action