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Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics
Theodore A Sarafian1, Shaghig Kouyoumjian, Farnaz Khoshaghideh
1Department of Medicine, Division of Pulmonary and Critical Care, Center for Health Sciences, University of California-Los Angeles, Los Angeles, CA 90095, USA. tsarafian@mednet.ucla.edu
Summary
Delta(9)-tetrahydrocannabinol (THC) rapidly depletes cellular energy and impairs mitochondrial function in lung cells. These effects on cellular energy stores and mitochondria suggest potential health consequences for the bronchopulmonary epithelium.
Area of Science:
- Cell Biology
- Toxicology
- Pharmacology
Background:
- Cellular energy depletion and mitochondrial dysfunction are critical factors in various diseases.
- Delta(9)-tetrahydrocannabinol (THC) is a primary psychoactive component of cannabis with known physiological effects.
- The impact of THC on pulmonary cell energy metabolism and mitochondrial integrity requires further elucidation.
Purpose of the Study:
- To investigate the effects of Delta(9)-tetrahydrocannabinol (THC) on cellular energy stores and mitochondrial function in the A549 pulmonary cell line.
- To determine the dose-dependency and time-course of THC-induced cellular and mitochondrial alterations.
- To elucidate the mechanisms underlying THC's effects on mitochondrial function, including potential involvement of the mitochondrial permeability transition pore.
Main Methods:
- Cellular viability and ATP levels were assessed following THC exposure.
- Mitochondrial membrane potential was evaluated using the JC-1 fluorescent probe.
- Flow cytometry was employed to analyze mitochondrial function in cells exposed to smoke extracts.
- Comparison with known mitochondrial inhibitors and the effect of cyclosporin A were investigated.
Main Results:
- THC caused a dose-dependent depletion of cellular ATP, with an IC(50) of 7.5 microg/ml after 24-h exposure.
- Significant mitochondrial dysfunction, indicated by diminished mitochondrial membrane potential, was observed at THC concentrations as low as 0.5 microg/ml.
- THC's effects on mitochondrial function mimicked uncoupling of electron transport and were suppressed by cyclosporin A, suggesting involvement of the mitochondrial permeability transition pore.
- These disruptions were sustained for at least 24-30 hours, even after THC removal.
Conclusions:
- THC exposure leads to rapid and extensive depletion of cellular energy stores in pulmonary cells.
- THC significantly impairs mitochondrial function, affecting membrane potential and potentially uncoupling electron transport.
- The observed mitochondrial disruption, mediated by the mitochondrial permeability transition pore, suggests significant health and physiological consequences for the bronchopulmonary epithelium upon THC exposure.