Caspase-independent cell death and mitochondrial disruptions observed in the Apaf1-deficient cells

K Miyazaki, H Yoshida, M Sasaki, H Hara… - The journal of …, 2001 - jstage.jst.go.jp
K Miyazaki, H Yoshida, M Sasaki, H Hara, G Kimura, TW Mak, K Nomoto
The journal of biochemistry, 2001jstage.jst.go.jp
Apaf1 is a critical molecule in the mitochondria-dependent apoptotic pathway. Here we
show that Apaf1-deficient embryonic fibroblasts died at a later phase of apoptotic induc tion,
although these cells were resistant to various apoptotic stimulants at an early phase. Neither
caspase 3 activation nor nuclear condensation was observed during this cell death of Apaf1-
deficient cells. Electron microscopic examination revealed that death in response to
apoptotic stimulation resembled necrosis in that nuclei were round and swollen with low …
Apaf1 is a critical molecule in the mitochondria-dependent apoptotic pathway. Here we show that Apaf1-deficient embryonic fibroblasts died at a later phase of apoptotic induc tion, although these cells were resistant to various apoptotic stimulants at an early phase. Neither caspase 3 activation nor nuclear condensation was observed during this cell death of Apaf1-deficient cells. Electron microscopic examination revealed that death in response to apoptotic stimulation resembled necrosis in that nuclei were round and swollen with low electron density. Necrosis-like cell death was also observed in wildtype cells treated with z-VAD-fink. Mitochondria were not only morphologically abnor mal but functionally affected, since mitochondrial transmembrane potential(•˘ ƒµm) was lost even in cells with intact plasma membrane integrity. These mitochondrial alter ations were also observed in the wild-type cells dying of apoptosis. Combined, these data suggest that cells without caspase activation, such as Apaf1-deficient cells or cells treated with caspase inhibitors, die of necrosis-like cell death with mitochondrial damage in response to" apoptotic stimulation."
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