GRANZYMES AND MITOCHONDRIA
Cytotoxic T-lymphocytes and natural killers eliminate infected cells from an 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 subsequent penetration into 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 mitochondria into cytoplasm, causing formation of apoptosomes that provide proteolytic cascade of caspases' activation. Granzymes M, H, and F cause cell death, which is accompanied by the release of cytochrome c from mitochondria. Granzyme A induces generation of reactive oxygen species, which promote translocation of the endoplasmic reticulum-associated SET complex to cell nucleus. In cell nucleus granzyme A cleaves the SET thus activating nucleases that cause single-strand DNA breaks. Granzymes A and B penetrate mitochondria and cut the complex I subunits of the respiratory chain. One of the complex I subunits is a target for the caspase-3 as well. Granzyme dependent damage to complex I leads to ROS generation and cell death.