Intracellular ATP, a switch in the decision between apoptosis and necrosis

Abstract

Regardless of whether apoptosis or necrosis are elicited by toxicants or by pathophysiological conditions they are considered 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. The execution of the death program seems to involve a relatively limited number of pathways. In many instances, their ordered execution results in characteristic morphological and biochemical changes termed apoptosis. However, some subroutines of the degradation program may not be active in all cases of cell death. Then, the morphological appearance of dying cells and some of their biochemical alterations differ from those of classical 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-empting 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.