Mitochondria play a critical role in initiating apoptosis by controlling the mitochondrial permeability transition (PT). PT is a key early event in the apoptotic process, leading to the loss of mitochondrial transmembrane potential (ΔΨm) and subsequent nuclear apoptosis. This process is demonstrated in a cell-free system where purified mitochondria and nuclei are combined, showing that PT-induced mitochondria can trigger chromatin condensation and DNA fragmentation. Pharmacological agents that induce PT enhance the apoptosis-inducing potential of mitochondria, while those that prevent PT inhibit nuclear apoptosis. Bcl-2, a proto-oncogene product, inhibits apoptosis by preventing PT, as evidenced by its localization in mitochondrial membranes and its ability to block PT in response to various stimuli. Mitochondria from cells undergoing apoptosis can transfer nuclear apoptosis to a cell-free system, highlighting their role in the apoptotic cascade. The study also shows that PT is a critical step in the regulation of apoptosis, with Bcl-2 acting as an endogenous inhibitor of PT. The findings suggest that PT is both necessary and sufficient for nuclear apoptosis, and that mitochondrial dysfunction can lead to apoptosis through mechanisms other than reactive oxygen species (ROS). The study underscores the importance of PT in apoptosis regulation and highlights the potential of targeting PT for therapeutic interventions.Mitochondria play a critical role in initiating apoptosis by controlling the mitochondrial permeability transition (PT). PT is a key early event in the apoptotic process, leading to the loss of mitochondrial transmembrane potential (ΔΨm) and subsequent nuclear apoptosis. This process is demonstrated in a cell-free system where purified mitochondria and nuclei are combined, showing that PT-induced mitochondria can trigger chromatin condensation and DNA fragmentation. Pharmacological agents that induce PT enhance the apoptosis-inducing potential of mitochondria, while those that prevent PT inhibit nuclear apoptosis. Bcl-2, a proto-oncogene product, inhibits apoptosis by preventing PT, as evidenced by its localization in mitochondrial membranes and its ability to block PT in response to various stimuli. Mitochondria from cells undergoing apoptosis can transfer nuclear apoptosis to a cell-free system, highlighting their role in the apoptotic cascade. The study also shows that PT is a critical step in the regulation of apoptosis, with Bcl-2 acting as an endogenous inhibitor of PT. The findings suggest that PT is both necessary and sufficient for nuclear apoptosis, and that mitochondrial dysfunction can lead to apoptosis through mechanisms other than reactive oxygen species (ROS). The study underscores the importance of PT in apoptosis regulation and highlights the potential of targeting PT for therapeutic interventions.