Granzymes and Mitochondria

Cytotoxic T lymphocytes and natural killer cells eliminate infected cells from the organism by triggering programmed cell death (apoptosis). The contents of the lytic granules of killer cells, including pore-forming proteins perforins and proteolytic enzymes granzymes, are released with the following penetration of the released proteins into the target cells. Granzyme B initiates mitochondria-dependent apoptosis via (i) proapoptotic Bid protein, (ii) Mcl-1 and Bim proteins, or (iii) p53 protein. As a result, cytochrome c is released from the mitochondria into the cytoplasm, causing formation of apoptosomes that initiate the proteolytic cascade of caspase activation. Granzymes M, H, and F cause cell death accompanied by the cytochrome c release from the mitochondria. Granzyme A induces generation of reactive oxygen species (ROS), which promotes translocation of the endoplasmic reticulum-associated SET complex to the nucleus where it is cleaved by granzyme A, leading to the activation of nucleases that catalyze single-strand DNA breaks. Granzymes A and B penetrate into the mitochondria and cleave subunits of the respiratory chain complex I. One of the complex I subunits is also a target for caspase-3. Granzyme-dependent damage to complex I leads to the ROS generation and cell death.