Mimosine-induced cell death and related chromatin changes

The non-protein amino acid mimosine has recently been shown to induce an unusual mode of cell death that differs from necrosis and apoptosis, the two fundamental schemes of cell death. The drug affects primarily the cell nucleus and induces first condensation of the chromatin into a regular network of fibrils and then gradual decondensation. The present study was performed to evaluate effective mimosine concentrations, time dependency of toxicity, and mimosine-related alterations of the chromatin, DNA and histones. To this end, primarily cultured carp hepatocytes were exposed to a wide range of mimosine (10(-1) to 10(-4) M) up to 12 h and investigated by means of light microscopy, electron microscopy, and histochemistry for DNA and histones. With 10(-1) M mimosine severe cytopathological transformations were obtained already after 3 h whereas 10(-2) M was cytotoxic only after 12 h. Lower concentrations were ineffective within the experimental period. Cytopathology started with condensation of the chromatin into a homogeneous network of ca. 25 nm wide fibrils and segregation of the nucleolus. In parallel, the nuclei were depleted from histones leaving the pattern of DNA fluorescence largely unchanged. The following period of chromatin decondensation was characterized by removal of electron-dense components from the condensed chromatin fibrils and gradual loss of the DNA. The segregated nucleolus and also the nuclear pores remained well preserved until final cell lysis.