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

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.

Arsenic trioxide triggers a regulated form of caspase-independent necrotic cell death via the mitochondrial death pathway

“…Moreover, As 2 O 3 -induced cell demise was not blocked in cells deficient for caspase-2 or -9. While caspase-9 is part of the apoptosome and therefore plays a key role during the mitochondrial pathway of apoptosis (Hu et al, 1999;Saleh et al, 1999;Zou et al, 1999), caspase-2 is currently discussed as an initiator caspase that might respond to DNA damage and activates the mitochondrial apoptosis machinery (Troy and Shelanski, 2003;Norbury and Zhivotovsky, 2004;Robertson et al, 2004). Nevertheless, our present data delineate that caspases appear to be dispensable for induction of cell death by As 2 O 3 .…”

boc-Aspartyl(OMe)-Fluoromethylketone Attenuates Mitochondrial Release of Cytochrome c and Delays Brain Tissue Loss after Traumatic Brain Injury in Rats

“…To determine whether the pan-caspase inhibitor BAF influenced caspases upstream of cytochrome c release, similar to in vitro studies (Lassus et al, 2002;Li et al, 1998;Robertson et al, 2004), cytosolic caspase-2 and caspase-8 proteolysis were evaluated 24 h after CCI in rats treated with 1000 nmol BAF or vehicle. Consistent with a regulatory role for caspase-2 in mitochondrial cytochrome c release, BAF treatment reduced caspase-2 proteolysis in ipsilateral cortex by > 50% compared with vehicle treatment, and also reduced caspase-2 proteolysis in ipsilateral hippocampus, but to a lesser degree than in cortex (Figures 3A and 3B; P < 0.05, t-test).…”

“…Recently, initiator caspases have been shown to be upstream regulators of cytochrome c release from the mitochondria. Under conditions of cell stress, caspase-2 permeabilizes the outer mitochondrial membrane facilitating cytochrome c release, an event requiring caspase-2 proteolysis but independent of its enzymatic activity (Lassus et al, 2002;Robertson et al, 2004). Activated caspase-8 can also result in cytochrome c release via truncation of the proapoptotic Bcl-2 family member Bid, with translocation of truncated Bid (tBid) into mitochondria (Henshall et al, 2001).…”

Androgen regulates apoptosis induced by TNFR family ligands via multiple signaling pathways in LNCaP

“…It has been shown that caspase-2 plays a prominent role in different cell death systems (reviewed by Degterev et al, 2003) including the release of apoptogenic factors from mitochondria directly (Guo et al, 2002;Lassus et al, 2002). It is interesting that processed caspase-2 can induce mitochondria-mediated apoptosis independent of its enzymatic activity (Robertson et al, 2004).…”