A molecular mechanism for mimosine-induced apoptosis involving oxidative stress and mitochondrial activation.
Mimosine, a non-protein amino acid, is mainly known for its action as a reversible inhibitor of DNA replication and, therefore, has been widely used as a cell cycle synchronizing agent. Recently, it has been shown that mimosine also induces apoptosis, as mainly reflected in its ability to elicit characteristic nuclear changes. The present study elucidates the mechanism underlying mimosine's apoptotic effects, using the U-937 leukemia cell line. We now demonstrate that in isolated rat liver mitochondria, mimosine induces mitochondrial swelling that can be inhibited by cyclosporine A, indicative of permeability transition (PT) mega-channel opening. Mimosine-induced apoptosis was accompanied by formation of hydrogen peroxide and a decrease in reduced glutathione levels. The apoptotic process was partially inhibited by cyclosporine A and substantially blocked by the antioxidant N-acetylcysteine, suggesting an essential role for reactive oxygen species formation during the apoptotic processes. The apoptosis induced by mimosine was also accompanied by a decrease in mitochondrial membrane potential, cytochrome c release and caspase 3 and 9 activation. Our results thus imply that mimosine activates apoptosis through mitochondrial activation and formation of H2O2, both of which play functional roles in the induction of cell death.
Institute of Hematology, Soroka University Medical Center, Beer Sheva, Israel.
Maher
M
Hallak
Liat
L
Vazana
Ofer
O
Shpilberg
Itai
I
Levy
Julia
J
Mazar
Ilana
I
Nathan
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008898:Mimosine / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D008898:Mimosine; D016572:Cyclosporine; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D020169:Caspases; D000111:Acetylcysteine