THE BIOCHEMISTRY OF PROGRAMMED CELL-DEATH

Programmed cell death (PCD) is involved in the removal of superfluous and damaged cells in most organ systems. The induction phase of PCD or apoptosis is characterized by an extreme heterogeneity of potential P CD-triggering signal transduction pathways. During the subsequent effe ctor phase, the numerous PCD-inducing stimuli converge into a few ster eotypical pathways and cells pass a point of no return, thus becoming irreversibly committed to death. It is only during the successive degr adation phase that vital structures and functions are destroyed, givin g rise to the full-blown phenotype of PCD. Evidence is accumulating th at cytoplasmic structures, including mitochondria, participate in the critical effector stage and that alterations commonly considered to de fine PCD (apoptotic morphology of the nucleus and regular, oligonucleo sonmal chromatin fragmentation) have to be ascribed to the late degrad ation phase. The decision as to 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 switches may reside in a perturbation of mitochondrial function. Thus, a decrea se in mitochondrial transmembrane potential, followed by mitochondrial uncoupling and generation of reactive oxygen species, precedes nuclea r alterations. It appears that molecules that participate in apoptotic decision-making also exert functions that are vital for normal cell p roliferation and intermediate metabolism.