Mitochondrial Entry of Cytotoxic Proteases: A New Insight into the Granzyme B Cell Death Pathway

Figure 1

Granzymes and caspase 3 enter the mitochondria through the Sam50 channel. Upon recognition of the target cell, the effector cell vectorially degranulates the cytotoxic granule content into the immunological synapse from where perforin, a pore forming protein, triggers membrane repair, which results in the internalization and delivery of the granzymes into the target cell cytosol. In the target cell cytosol, granzymes initiate cell death by cleaving various substrates. Both granzymes and caspase 3 cross the outer and the inner mitochondrial membrane through the Sam50 and Tim22 channels, respectively. Once in the matrix, granzyme and caspase 3 disrupt the electron transport chain (ETC) complex I and trigger ROS mediation of cell death.