Energy supply and the shape of death in neurons and lymphoid cells

Abstract

Apoptosis and necrosis are considered as conceptually distinct forms of cell death. Nevertheless, there is increasing evidence that classical apoptosis and necrosis represent only the extreme ends of a wide range of possible morphological and biochemical deaths. The two classical types of demise can occur simultaneously in tissues or cell cultures exposed to the same stimulus, and often the intensity of the same initial insult decides the prevalence of either apoptosis or necrosis. This suggests that, while some early events may be common to both types of cell death, a downstream controller may be required to direct cells towards the organised execution of apoptosis. We have recently shown that intracellular energy levels and mitochondrial function are rapidly compromised in necrosis, but not in apoptosis of neuronal cells. Then, we went on to show that pre-emptying human T cells of ATP switches the type of demise caused by two classic apoptotic triggers (staurosporin and CD95 stimulation) from apoptosis to necrosis. Conditions of controlled intracellular ATP depletion, which was obtained by blocking mitochondrial and/or glycolytic ATP generation, were used in combination with repletion of the cytosolic ATP pool with glucose to redirect the death program towards apoptosis or necrosis. At least two distinct steps, the typical nuclear degradation, and the expression of annexin V-recognisable determinants on the cell surface require sufficient ATP generation. This suggests that some upstream regulators of cell death may be common to both types of cell demise, whereas yet unknown downstream processes decide its shape and the implications for the neighbouring tissue.

Mitochondrial implication in apoptosis. Towards an endosymbiont hypothesis of apoptosis evolution

“…This scenario would be compatible with the finding that many drugs induce necrosis at high doses and apoptosis at lower (`subnecrotic') doses (Kroemer, 1995). It would also be compatible with the observation that modulation of ATP levels can shift the balance between apoptosis and necrosis to one or the other mode of cell death (see accompanying reviews by Nicotera and Leist, 1997;Tsujimoto, 1997). Finally, it would explain why cells in which the activation of most if not all caspases is inhibited by means of the inhibitor Z-VAD.fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluromethylketone) undergo nonapoptotic (necrotic?)…”

Apoptosis and necrosis: Intracellular ATP level as a determinant for cell death modes

“…Depletion of intracellular ATP by incubating cells in glucose-free medium to halt glycolysis, in the presence of the mitochondrial F 0 F 1 -ATPase inhibitor oligomycin, completely blocked apoptosis induced by Fas stimulation, VP16, dexamethasone or calcium ionophore, and ATP supplied through either glycolysis or mitochondrial oxidative phosphorylation restored the apoptotic cell death pathway, indicating that apoptosis is ATP-dependent . The same conclusion was also reached by (discussed by Nicotera and Leist, 1997). Shimizu et al, (1995d), measured intracellular ATP levels during cell death, and shown that intracellular ATP levels remain unchanged until the very end of apoptotic process such as disruption of plasma membrane.…”

Time-dependent effects of imatinib in human leukaemia cells: a kinetic NMR-profiling study

“…Cell shrinkage, DNA damage, chromatin condensation and blebbing of the plasma and alteration of plasma membrane phospholipid organisation with phosphatidylserine externalisation are major characteristics of apoptosis (Williams, 1991;Wood and Youle, 1994). Necrosis is generally characterised by swelling of cells and mitochondria, scattered chromatin condensation and loss of plasma membrane integrity because of an overwhelming physical cell injury (Williams, 1991;Nicotera and Leist, 1997).…”