Complex I dysfunction and tolerance to nitroglycerin: an approach based on mitochondrial-targeted antioxidants

Area of Science:

• Pharmacology
• Mitochondrial Biology
• Cardiovascular Research

Background:

• Nitroglycerin (GTN) is widely used for angina, but tolerance limits its chronic efficacy.
• The mechanisms underlying GTN tolerance, particularly mitochondrial dysfunction, remain incompletely understood.
• Oxidative stress within mitochondria is implicated in various pathological conditions.

Purpose of the Study:

• To investigate the role of mitochondrial function and oxidative stress in the development of GTN tolerance.
• To identify specific mitochondrial targets affected by prolonged GTN exposure.
• To evaluate the potential of mitochondrial-targeted antioxidants in preventing GTN tolerance.

Main Methods:

• Induction of GTN tolerance in vivo (rats) and in vitro (vessels, endothelial cells).
• Electrochemical detection of nitric oxide (NO) and oxygen (O2) consumption.
• Assessment of mitochondrial respiration, aldehyde dehydrogenase (ALDH)-2 activity, and reactive oxygen species (ROS) production.
• Intervention with mitochondrial-targeted antioxidants (mitoquinone [MQ]) and glutathione (GSH) ester.

Main Results:

• GTN tolerance decreased mitochondrial O2 consumption and altered its kinetics (Km) in a noncompetitive manner.
• Tolerance was associated with aldehyde dehydrogenase (ALDH)-2 inhibition and mitochondrial uncoupling.
• Mitochondrial-targeted antioxidants (MQ) and GSH ester prevented tolerance and protected mitochondrial function and ALDH-2 activity.
• GTN's effects on mitochondrial respiration were primarily linked to Complex I inhibition, mediated by ROS.

Conclusions:

• Prolonged GTN treatment induces tolerance by impairing mitochondrial Complex I function via ROS-mediated oxidative stress.
• Aldehyde dehydrogenase (ALDH)-2 inhibition and Complex I dysfunction are key mechanisms in GTN tolerance.
• Mitochondrial-targeted antioxidants show promise as a therapeutic strategy to mitigate chronic nitrate tolerance.