Ceramide Permeabilization of Mitochondrial Outer Membrane: Pharmacological Characterization and Relation to Mac and Bax
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Title of Document: CERAMIDE PERMEABILIZATION OF MITOCHONDRIAL OUTER MEMBRANE: PHARMACOLOGICAL CHARACTERIZATION AND RELATION TO MAC AND BAX Suzanne J. Hudak, Master of Science, 2005 Directed By: Dr. Marco Colombini, Professor, Biology and Biochemistry Departments In apoptosis, the mitochondrial outer membrane (MOM) becomes permeable, releasing proteins. This permeability has been attributed to the action of various factors, including mitochondrial apoptosis-induced channel (MAC), Bax and ceramide channels. Amphiphilic cations that inhibited MAC and Bax-induced permeabilization were tested on ceramide-induced permeabilization of MOM of mammalian and yeast mitochondria, as well as liposomes. Both propranolol and dibucaine inhibited C2and C16-ceramide-induced permeabilization of mammalian MOM with an IC50 for C16-ceramide of 410 and 230 μM, respectively. In yeast mitochondria, propranolol and dibucaine inhibited C2-ceramide-induced permeabilization, but potentiated the effect of C16-ceramide. Similar results were obtained in liposome experiments. These results suggest that inhibition is via another factor found in mammalian cells but not the other systems. The pharmacology of ceramide membrane permeabilization is inconsistent with that of MAC but is compatible to that of Bax. CERAMIDE PERMEABILIZATION OF MITOCHONDRIAL OUTER MEMBRANE: PHARMACOLOGICAL CHARACTERIZATION AND RELATION TO MAC AND BAX
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