Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose

Abstract

Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose in vitro in human cells using detailed respirometric analysis revealed that complex I-linked (NADH-dependent) but not complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury.

Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity

“…Metformin and acetaminophen are widely used drugs which, similarly to statins, have been reported to inhibit the NADH-supported mitochondrial respiration and this unfavorable effect has been recently overcome by the use of cell-permeable succinate [ 19 , 20 ]. Similarly, the NADH-linked mitochondrial respiratory impairment caused by cerivastatin and atorvastatin in the present study was counteracted by means of a cell-permeable succinate prodrug, NV118 that bypassed the mitochondrial dysfunction and recovered the coupled (ATP-generating) respiration.…”

“…Studies in isolated mitochondria in the LEAK state have shown that when supplied with saturating levels of succinate part of the electron flow is reversed and travels back through complex I generating reactive oxygen species (ROS) [ 56 ]. However, the risk of ROS increases through this mechanism seem to be low in the presence of complex I inhibition, which is exactly when cell-permeable succinates should be used [ 20 , 57 ].…”

“…Cell-permeable succinates can be used as a means to stimulate succinate supported respiration, eliminating the need for electron transfer through the impaired mitochondrial complex I whether it is induced by statins or other compounds, as has been shown previously [ 18 , 19 , 20 ]. As such, this makes cell-permeable succinates promising candidates for the treatment of SAMS.…”

“…In order to bypass this complex I defect, enhancing complex II (succinate)-dependent respiration could be a viable approach. However, the dicarboxylic acid succinate displays a very limited cellular uptake, a disadvantage that has been recently overcome by using cell-permeable succinate prodrugs in various conditions associated with impairment of NADH-supported respiration [ 18 , 19 , 20 ].…”

Improvement of Platelet Respiration by Cell–Permeable Succinate in Diabetic Patients Treated with Statins

“…Cell–permeable succinates have been successfully used to rescue mitochondrial respiration in experimental models of acute complex I inhibition [ 21 , 22 ]. We recently showed in acute experiments using human platelets and HepG2 cells that a cell–permeable succinate prodrug, NV118, can bypass complex I mitochondrial dysfunction induced by statins [ 23 ].…”