The article by Zamzami et al. explores the role of mitochondria in the control of nuclear apoptosis, a process that occurs independently of the nucleus. Mitochondria have been shown to participate in the cytoplasmic control of apoptotic nuclear disintegration. The authors present evidence that mitochondrial permeability transition (PT) pores, which open under certain conditions, are a critical early event in the apoptotic process. In a cell-free system, mitochondria undergoing PT induce chromatin condensation and DNA fragmentation. Pharmacological agents that induce PT augment the apoptosis-inducing potential of mitochondria, while those that prevent PT impede nuclear apoptosis both in vitro and in vivo. Mitochondria from hepatocytes or lymphoid cells undergoing apoptosis, but not normal cells, induce the disintegration of isolated HeLa nuclei. Bongreic acid, a specific ligand of the mitochondrial adenine nucleotide translocator (ANT), inhibits PT and reduces apoptosis induction by mitochondria. The proto-oncogene product Bcl-2, which is localized in the mitochondrial outer membrane, inhibits apoptosis by preventing mitochondrial PT. These findings establish mitochondrial PT as a critical step in the apoptotic cascade.The article by Zamzami et al. explores the role of mitochondria in the control of nuclear apoptosis, a process that occurs independently of the nucleus. Mitochondria have been shown to participate in the cytoplasmic control of apoptotic nuclear disintegration. The authors present evidence that mitochondrial permeability transition (PT) pores, which open under certain conditions, are a critical early event in the apoptotic process. In a cell-free system, mitochondria undergoing PT induce chromatin condensation and DNA fragmentation. Pharmacological agents that induce PT augment the apoptosis-inducing potential of mitochondria, while those that prevent PT impede nuclear apoptosis both in vitro and in vivo. Mitochondria from hepatocytes or lymphoid cells undergoing apoptosis, but not normal cells, induce the disintegration of isolated HeLa nuclei. Bongreic acid, a specific ligand of the mitochondrial adenine nucleotide translocator (ANT), inhibits PT and reduces apoptosis induction by mitochondria. The proto-oncogene product Bcl-2, which is localized in the mitochondrial outer membrane, inhibits apoptosis by preventing mitochondrial PT. These findings establish mitochondrial PT as a critical step in the apoptotic cascade.