Inhibition of mitochondrial ATP generation by nitric oxide switches apoptosis to necrosis.
Under pathological conditions, the mode of cell death, apoptosis or necrosis, is relevant for the subsequent fate of the tissue. Cell demise may be shaped by endogenous mediators such as nitric oxide (NO) which interfere with subroutines of the death program. Here we show that apoptosis of Jurkat cells elicited by either staurosporine (STS) or anti-CD95 antibodies in glucose-free medium is converted to necrosis by NO donors. In the presence of NO, release of mitochondrial cytochrome c was delayed and activation of execution caspases was prevented. Stimulated cells died nonetheless. The switch in the mode of cell death was due to NO-dependent failure of mitochondrial energy production. Restoration of intracellular ATP by glucose supplementation recovered the cells' ability to activate caspases and undergo apoptosis. In this system, the apoptosis/necrosis conversion promoted by NO was not mediated by cyclic guanosine monophosphate-dependent mechanisms, poly-(ADP-ribose)-polymerase (PARP) activation, or inhibition of caspases due to S-nitrosylation and glutathione depletion. In contrast, depleting intracellular ATP with rotenone, an inhibitor of mitochondrial complex I mimicked the effect of NO. The findings presented here suggest that NO can decide the shape of cell death by lowering intracellular ATP below the level required to allow the coordinated execution of apoptosis.
Leist
M
M
Chair of Molecular Toxicology, Faculty of Biology, University of Konstanz, Konstanz, D-78457, Germany.
Single
B
B
Naumann
H
H
Fava
E
E
Simon
B
B
Kühnle
S
S
Nicotera
P
P
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology* / Q000502:physiology; D009336:Necrosis; D009569:Nitric Oxide / Q000502:physiology*
D003574:Cytochrome c Group; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D020169:Caspases