Flow Cytometric Measurements Of The Early Biochemical Events Of The Programed Cell Death.
P.X. Petit*, N. Zamzami**, J.L. Vayssière, B. Mignotte, G. Kroemer**, Centre de Génétique Moléculaire, C.N.R.S., F-91190 Gif-sur-Yvette and **C.N.R.S., UPR 420, F-94801 Villejuif, France.
Programmed cell death (PCD) obeys a biological strategy to canalize cells that trespass a critical threshold of entropy towards an ordered process of catabolism and removal. The induction phase of PCD is characterized by an extreme heterogeneity of potential PCD-triggering signal transduction pathways. During the subsequent effector phase, the numerous PCD-inducing stimuli converge into a few stereotypical pathways and cells pass a point-of-no-return, thus becoming irreversibly committed to death. It is only during the successive degradation phase that vital structures and functions are destroyed, giving rise to the full-blown phenotype of PCD. Evidence is accumulating that cytoplasmic structures including mitochondria participate in the critical effector stage and that alterations that are commonly considered to define PCD-apoptotic morphology of the nucleus and chromatin fragmentation-have to be ascribed to the late degradation phase. The decision whether a cell will undergo PCD or not may be expected to be regulated by "switches" that, once activated, trigger self-amplificatory metabolic pathways. One of these early switches may involve mitochondrial permeability transition. Thus, a decrease in mitochondria transmembrane potential, followed by mitochondrial uncoupling, generation of reactive oxygen species, leakage of Ca2+ and of glutathion precedes nuclear alterations. It appears that molecules that participate in apoptotic decision-making also exert functions that are vital for normal cell proliferation and intermediate metabolism.