MAC inhibitors suppress mitochondrial apoptosis.
MAC (mitochondrial apoptosis-induced channel) forms in the mitochondrial outer membrane and unleashes cytochrome c to orchestrate the execution of the cell. MAC opening is the commitment step of intrinsic apoptosis. Hence closure of MAC may prevent apoptosis. Compounds that blocked the release of fluorescein from liposomes by recombinant Bax were tested for their ability to directly close MAC and suppress apoptosis in FL5.12 cells. Low doses of these compounds (IC50 values ranged from 19 to 966 nM) irreversibly closed MAC. These compounds also blocked cytochrome c release and halted the onset of apoptotic markers normally induced by IL-3 (interleukin-3) deprivation or staurosporine. Our results reveal the tight link among MAC activity, cytochrome c release and apoptotic death, and indicate this mitochondrial channel is a promising therapeutic target.
Peixoto
Pablo M
PM
Department of Basic Sciences, New York University College of Dentistry, New York, NY 10010, USA.
Ryu
Shin-Young
SY
Bombrun
Agnes
A
Antonsson
Bruno
B
Kinnally
Kathleen W
KW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000494:pharmacology*
C494827:Bax protein, mouse; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D007473:Ion Channels; D049990:Membrane Transport Modulators; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D019311:Staurosporine