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Published on: February 10, 2022
Inhibition of monoamine oxidase-a increases respiration in isolated mouse cortical mitochondria
Olivia J Kalimon1, Hemendra J Vekaria1, Greg A Gerhardt2
1Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40356, USA; Department of Neuroscience, University of Kentucky, Lexington, KY 40508, USA; Lexington VA Healthcare System, Lexington, KY 40502, USA.
Abstract:
Monoamine oxidase (MAO) is an enzyme located on the outer mitochondrial membrane that metabolizes amine substrates like serotonin, norepinephrine and dopamine. MAO inhibitors (MAOIs) are frequently utilized to treat disorders such as major depression or Parkinson's disease (PD), though their effects on brain mitochondrial bioenergetics are unclear. These studies measured bioenergetic activity in mitochondria isolated from the mouse cortex in the presence of inhibitors of either MAO-A, MAO-B, or both isoforms. We found that only 10 μM clorgyline, the selective inhibitor of MAO-A and not MAO-B, increased mitochondrial oxygen consumption rate in State V(CI) respiration compared to vehicle treatment. We then assessed mitochondrial bioenergetics, reactive oxygen species (ROS) production, and Electron Transport Chain (ETC) complex function in the presence of 0, 5, 10, 20, 40, or 80 μM of clorgyline to determine if this change was dose-dependent. The results showed increased oxygen consumption rates across the majority of respiration states in mitochondria treated with 5, 10, or 20 μM with significant bioenergetic inhibition at 80 μM clorgyline. Next, we assessed mitochondrial ROS production in the presence of the same concentrations of clorgyline in two different states: high mitochondrial membrane potential (ΔΨm) induced by oligomycin and low ΔΨm induced by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP). There were no changes in ROS production in the presence of 5, 10, 20, or 40 μM clorgyline compared to vehicle after the addition of oligomycin or FCCP. There was a significant increase in mitochondrial ROS in the presence of 80 μM clorgyline after FCCP addition, as well as reduced Complex I and Complex II activities, which are consistent with inhibition of bioenergetics seen at this dose. There were no changes in Complex I, II, or IV activities in mitochondria treated with low doses of clorgyline. These studies shed light on the direct effect of MAO-A inhibition on brain mitochondrial bioenergetic function, which may be a beneficial outcome for those taking these medications.
Insights
Monoamine oxidase A (MAO-A) inhibition by clorgyline enhances brain mitochondrial respiration at low doses. Higher doses of MAO-A inhibition lead to mitochondrial dysfunction and reactive oxygen species production.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Monoamine oxidase (MAO) enzymes, specifically MAO-A and MAO-B, are crucial for metabolizing neurotransmitters like serotonin and dopamine.
- MAO inhibitors (MAOIs) are used to treat neurological and psychiatric disorders, but their precise impact on brain mitochondrial function remains incompletely understood.
- Understanding MAOI effects on mitochondrial bioenergetics is vital for optimizing therapeutic strategies and minimizing side effects.
Purpose of the Study:
- To investigate the direct effects of MAO-A inhibition on the bioenergetic activity of mouse cortical mitochondria.
- To determine the dose-dependent responses of mitochondrial respiration, reactive oxygen species (ROS) production, and electron transport chain (ETC) complex activity to clorgyline, a selective MAO-A inhibitor.
- To elucidate the potential benefits or risks associated with MAO-A inhibition on mitochondrial health.
Main Methods:
- Mitochondria were isolated from mouse cortex and their bioenergetic activity was measured using respirometry in the presence of varying concentrations of clorgyline (a selective MAO-A inhibitor).
- Oxygen consumption rates, mitochondrial membrane potential (ΔΨm), and ROS production were assessed under different respiratory states.
- Activities of ETC complexes I, II, and IV were evaluated to determine the impact of clorgyline on mitochondrial energy production pathways.
Main Results:
- Low concentrations of clorgyline (5-20 μM) significantly increased mitochondrial oxygen consumption rates, particularly in State V(CI) respiration, indicating enhanced bioenergetic function.
- Higher concentrations (80 μM) of clorgyline resulted in significant inhibition of mitochondrial bioenergetics, reduced ETC complex activities (Complex I and II), and increased ROS production, especially after FCCP-induced dissipation of ΔΨm.
- No significant changes in ROS production or ETC complex activities were observed at lower, respiration-enhancing doses of clorgyline.
Conclusions:
- Selective MAO-A inhibition by clorgyline can enhance brain mitochondrial respiration at specific, low concentrations, suggesting a potential therapeutic benefit.
- High-dose MAO-A inhibition leads to mitochondrial dysfunction, characterized by impaired energy production and increased oxidative stress, highlighting a dose-dependent safety concern.
- These findings provide critical insights into the direct impact of MAO-A inhibition on neuronal mitochondria, informing the clinical use of MAOIs in treating conditions like Parkinson's disease and depression.
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