Please use this identifier to cite or link to this item:
|Title:||Lopimune-induced mitochondrial toxicity is attenuated by increased uncoupling protein-2 level in treated mouse hepatocytes||Authors:||Hoss, Sara El
Bahr, George M.
|Affiliations:||Faculty of Medicine
Faculty of Medicine
|Issue Date:||2015||Part of:||Biochemical journal||Volume:||468||Issue:||3||Start page:||401||End page:||407||Abstract:||
Although the protease inhibitor (PI) Lopimune has proven to be effective, no studies have examined the side effects of Lopimune on mitochondrial bioenergetics in hepatocytes. The objective of the present study is to evaluate mitochondrial respiration, production of reactive oxygen species (ROS) and expression of uncoupling protein-2 (UCP2) in mouse hepatocytes following Lopimune administration. Mitochondria were extracted from mouse liver using differential centrifugation and hepatocytes were isolated by the collagenase perfusion procedure. Mitochondrial respiration was measured using a Rank Brothers oxygen electrode. ROS production in hepatocytes was monitored by flow cytometry using a 2ʹ,7ʹ-dichlorofluorescin diacetate probe and UCP2 protein expression was detected by Western blotting. We found that Lopimune induced a significant decrease of approximately 30% in the respiratory control ratio (RCR) starting from day 4 until day 9 of treatment. This decrease was due to an increase in state 4 respiration, reflecting an increase in mitochondrial proton leak. State 2 and state 3 respirations were not affected. Moreover, ROS production significantly increased by about 2-fold after day 1 of treatment and decreased after day 3, returning to the resting level on day 5. Interestingly, UCP2 which is absent from control hepatocytes, was expressed starting from day 4 of treatment. Our findings indicate that Lopimune-induced proton leak, mediated by UCP2, may represent a response to inhibit the production of ROS as a negative feedback regulatory mechanism. These results imply a potential involvement of UCP2 in the regulation of oxidative stress and add new insights into the understanding of mitochondrial toxicity induced by PIs.
|Appears in Collections:||Faculty of Medicine|
Show full item record
checked on May 8, 2021
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.