title: Muramyl-dipeptide-induced mitochondrial proton leak in macrophages is associated with upregulation of uncoupling protein 2 and the production of reactive oxygen and reactive nitrogen species.
abstract: The synthetic immunomodulator muramyl dipeptide (MDP) has been shown to induce, in vivo, mitochondrial proton leak. In the present work, we extended these findings to the cellular level and confirmed the effects of MDP in vitro on murine macrophages. The macrophage system was then used to analyse the mechanism of the MDP-induced mitochondrial proton leak. Our results demonstrate that the cellular levels of superoxide anion and nitric oxide were significantly elevated in response to MDP. Moreover, isolated mitochondria from cells treated with MDP presented a significant decrease in respiratory control ratio, an effect that was absent following treatment with a non-toxic analogue such as murabutide. Stimulation of cells with MDP, but not with murabutide, rapidly upregulates the expression of the mitochondrial protein uncoupling protein 2 (UCP2), and pretreatment with vitamin E attenuates upregulation of UCP2. These findings suggest that the MDP-induced reactive species upregulate UCP2 expression in order to counteract the effects of MDP on mitochondrial respiratory efficiency.
authors: Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon.
authors: Takla G
authors: TG
authors: El-Khoury
authors: Georges M
authors: GM
authors: Bahr
authors: Karim S
authors: KS
authors: Echtay
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D007155:Immunologic Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014475:Uncoupling Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000071246:Uncoupling Protein 2; D015854:Up-Regulation / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D007155:Immunologic Factors; D007473:Ion Channels; D024101:Mitochondrial Proteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2; D014810:Vitamin E; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C033575:murabutide