Functional dissociation of Δψm and cytochrome c release defines the contribution of mitochondria upstream of caspase activation during granzyme B-induced apoptosis

Abstract

Loss of Bid confers clonogenic survival to granzyme B-treated cells, however the exact role of Bid-induced mitochondrial damage - upstream or downstream of caspases - remains controversial. Here we show that direct cleavage of Bid by granzyme B, but not caspases, was required for granzyme B-induced apoptosis. Release of cytochrome c and SMAC, but not AIF or endonuclease G, occurred in the absence of caspase activity and correlated with the onset of apoptosis and loss of clonogenic potential. Loss of mitochondrial trans-membrane potential (Δψm) was also caspase independent, however if caspase activity was blocked the mitochondria regenerated their Δψm. Loss of Δψm was not required for rapid g..