Caspase-independent cell death: leaving the set without the final cut

Abstract

Apoptosis is dependent upon caspase activation leading to substrate cleavage and, ultimately, cell death. Although required for the apoptotic phenotype, it has become apparent that cells frequently die even when caspase function is blocked. This process, termed caspase-independent cell death (CICD), occurs in response to most intrinsic apoptotic cues, provided that mitochondrial outer membrane permeabilization has occurred. Death receptor ligation can also trigger a form of CICD termed necroptosis. In this review, we will examine the molecular mechanisms governing CICD, highlight recent findings demonstrating recovery from conditions of CICD and discuss potential pathophysiological functions of these processes.

Figure 1. Death receptor activated necroptosis

When caspase activity is blocked, death receptor activation can drive necroptosis through upregulation of PLA₂ activity that, in turn, increases oxidative stress. RIP-1 kinase is also activated triggering necroptosis by directly acting upon mitochondrial function or, perhaps, by effecting autophagy.

Figure 2. Mitochondrial roles in caspase independent cell death

In the absence of caspase activity, following mitochondrial outer membrane permeabilization (MOMP) various mitochondrial intermembrane space proteins are released triggering loss of mitochondrial function and/or pro-actively contributing to cell death. Simultaneously, mitochondrial fission is activated and fusion inactivated thereby disrupting mitochondrial morphology. Collectively, these events contribute to caspase independent cell death (CICD).