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/H 2 O 2 ) production by acting as a specific inhibitor of ROS production at the I Q 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/H 2 O 2 . 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.

Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies

“…Currently, these inhibitors are generally grouped into two classes, according to the conformation of the CoQ site (I Q ): the ROS-inducing class A is an antagonist of the CoQ substrate and, the ROS-preventing class B is an antagonist of the QoQ H2 product [334]. It is worth noting, however, that the ROS-generation is heavily modulated not only by the class of the inhibitor but also by the site it occupies, available substrates and their concentrations and whether the condition is ischemia or reperfusion [334,335,336].…”

“…Therefore, many groups are studying reversible inhibitors, exploiting the advantage of a transiently inactivate complex I without the harm of permanent loss of activity. In this category, some compounds show good results in attenuating IRI in the rat/mouse myocardium: amobarbital (amytal) [250,343], S-nitroso-2-mercaptopropionyl glycine [344], MitoSNO [345] and OP2113 (anetholtrithion) [336]. Also, already cited in this review, metformin has been proven recently to be cardioprotective also as a modulator of complex-I.…”

Riding the tiger – physiological and pathological effects of superoxide and hydrogen peroxide generated in the mitochondrial matrix

“…The best of the published S1QELs and S3QELs have high potencies (low IC 50 s) in mitochondrial assays: S1QEL1.1, 70 nM (Brand et al 2016); S3QEL3, 350 nM (Orr et al 2015), and cause no inhibition of cell growth or the electron transport chain at 20 times higher concentrations. Other S1QELs with lower potencies have also been discovered: anethole trithione (5-[p-methoxyphenyl]-1,2-dithiole-3-thione, Sulfarlem V R , OP2113), IC 50 ¼ 10-26 mM (Boucard et al 2019;Detaille et al 2019), and Imeglimin, IC 50 ¼ $100 mM (Detaille et al 2016). However, it is unclear whether the S1QEL activities of anethole trithione (a known slow-release H 2 S donor (Wallace et al 2018)) or Imeglimin are the only cause of their biological effects.…”

Physiologic Implications of Reactive Oxygen Species Production by Mitochondrial Complex I Reverse Electron Transport

“…During RET, one of the ROS production sites in complex I is the Q binding site (IQ) [75]. There are many small molecules called suppressors of complex I site I(Q) electron leak (S1QELs), that inhibit complex I at this site, preventing ROS production and protecting against IR injury [70,76,77]. The onset of IR events is unpredictable, however.…”