An Old Medicine As A New Drug To Prevent Mitochondrial Complex I From Producing Oxygen Radicals

LeeLemonoil

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An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals

Abstract
Findings
Here, we demonstrate that OP2113 (5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione, CAS 532-11-6), synthesized and used as a drug since 1696, does not act as an unspecific antioxidant molecule (i.e., as a radical scavenger) but unexpectedly decreases mitochondrial reactive oxygen species (ROS/H2O2) production by acting as a specific inhibitor of ROS production at the IQ site of complex I of the mitochondrial respiratory chain. Studies performed on isolated rat heart mitochondria also showed that OP2113 does not affect oxidative phosphorylation driven by complex I or complex II substrates. We assessed the effect of OP2113 on an infarct model of ex vivo rat heart in which mitochondrial ROS production is highly involved and showed that OP2113 protects heart tissue as well as the recovery of heart contractile activity.

Conclusion / Significance
This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H2O2. OP2113 therefore appears to be a member of the new class of mitochondrial ROS blockers (S1QELs) and could protect mitochondrial function in numerous diseases in which ROS-induced mitochondrial dysfunction occurs. These applications include but are not limited to aging, Parkinson’s and Alzheimer's diseases, cardiac atrial fibrillation, and ischemia-reperfusion injury.
 

yerrag

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How do you interpret this statement: "Maximal ROS production occurs under conditions of high reduction of electron transporters, chiefly quinones, and high membrane potential values. Paradoxically, these conditions are satisfied when mitochondrial oxidative phosphorylation is low (low cellular ATP turnover) [25, 26] or under low oxygen conditions (hypoxia, inhibition of terminal oxidase) [13]."

I have a hard time understanding this as it seems to be saying that maximal ROS production occurs when mitochondrial oxidative phosphorylation is low. How can this be? When mitochondrial respiration is down-regulated, shouldn't ROS production be down-regulated as well?

Or is the author saying that under hypoxia, where anaerobic glycolysis occurs, a lot of ROS is produced, and under this conditon, mitochondrial respiration is inhibited (and as a result down-regulated)?

Or this could be just above my pay-grade.

Anyway, thanks for sharing this. It's very interesting and I'd like to try this on myself, if I can source it out. I have low heart rate indicative of low metabolism, which I suspect to be an adaptation by the body to match my mitochondrial respiratory rate to the available antioxidants (GSH) in my system. I'm likely low on anti-oxidant stores, as a result of these being redirected towards countering the excess ROS spillover from the respiratory burst of phagocytosis of chronic bacterial infetion by neutrophils and macrophages.

This could be useful for my context, as OP2113 could make up for my lack of antioxidant stores and in this way it would enable my mitochondrial respiration to rev up,
 
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