Evidence for a relationship between mitochondrial Complex I activity and mitochondrial aldehyde dehydrogenase during nitroglycerin tolerance: Effects of mitochondrial antioxidants

The medical use of nitroglycerin (GTN) is limited by patient tolerance. The present study evaluated the role of mitochondrial Complex I in GTN biotransformation and the therapeutic effect of mitochondrial antioxidants. The development of GTN tolerance (in rat and human vessels) produced a decrease in mitochondrial O2 consumption. Co-incubation with the mitochondria-targeted antioxidant mitoquinone (MQ, 10− 6 mol/L) or with glutathione ester (GEE, 10− 4 mol/L) blocked GTN tolerance and the effects of GTN on mitochondrial respiration and aldehyde dehydrogenase 2 (ALDH-2) activity. Biotransformation of GTN depended on the mitochondria being functionally active, particularly mitochondrial Complex I. Tolerance induced mitochondrial ROS production and oxidative stress, though these effects were not detected in HUVECρ0 cells or Complex I mutant cells. Experiments performed to evaluate Complex I-dependent respiration demonstrated that its inhibition by GTN was prevented by the antioxidants in control samples. These results point to a key role for mitochondrial Complex I in the adequate functioning of ALDH-2. In addition, we have identified mitochondrial Complex I as one of the targets at which the initial oxidative stress responsible for GTN tolerance takes place. Our data also suggest a role for mitochondrial-antioxidants as therapeutic tools in the control of the tolerance that accompanies chronic nitrate use.

► Mitochondrial Complex I is undermined following continuous exposure to GTN.
► GTN induces oxidative stress, with mitochondria both its source and its target.
► Complex I plays a role in GTN biotransformation particularly regarding ROS production.
► Complex I can regulate ALDH-2 activity through the availability of NAD+.
► Mitochondrial-antioxidants show a therapeutic effect in the control of the tolerance that accompanies chronic nitrate use.