Processed caspase‐2 can induce mitochondria‐mediated apoptosis independently of its enzymatic activity

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Abstract
The mechanism by which caspase‐2 executes apoptosis remains obscure. Recent findings indicate that caspase‐2 is activated early in response to DNA‐damaging antineoplastic agents and may be important for the engagement of the mitochondrial apoptotic pathway. We demonstrate here that fully processed caspase‐2 stimulates mitochondrial release of cytochrome c and Smac/DIABLO, but not apoptosis‐inducing factor (AIF). This event occurs independently of several Bcl‐2 family proteins, including Bax, Bak and Bcl‐2, and inactivation experiments reveal that the proteolytic activity of caspase‐2 is not required for the effect. Further, functional studies of mitochondria indicate that processed caspase‐2 stimulates state 4 respiration and decreases the respiratory control ratio as a result of, in large part, an uncoupling effect. Combined, our data suggest that caspase‐2 retains a unique ability to engage directly the mitochondrial apoptotic pathway, an effect that requires processing of the zymogen but not the associated catalytic activity.