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.