Cell death: a Biomedical paradigm

Mitochondrial outer membrane permeabilization is often required for activation of the caspase proteases that cause apoptotic cell death. As a consequence, the integrity of the mitochondrial outer membrane is highly controlled, primarily through interactions between pro- and anti-apoptotic members of the B cell lymphoma 2 (BCL-2) protein family.

Although necrosis was regarded as an uncontrolled mode of cell death, evidence now shows that it can be highly regulated. The initiation of programmed necrosis (necroptosis) by death receptors requires receptor-interacting protein 1 (RIP1) and RIP3, and its execution involves the active disintegration of mitochondrial, lysosomal and plasma membranes.

Metabolic pathways such as glycolysis and the pentose phosphate pathway communicate to cell cycle and apoptotic effectors, including D-type cyclins, CDKs, APC, p53, caspase 2 and BCL-2 proteins. The importance of this crosstalk is emphasized by the role of metabolic aberrations in the aetiology of disease.

The regulation of apoptosis is essential for cell homeostasis and the survival of multicellular organisms, and excessive or diminished apopotosis can contribute to various diseases. The post-translational modification of apoptotic proteins by ubiquitylation is a key regulatory mechanism of cell death signalling cascades. Targeting apoptotic regulatory proteins in the ubiquitin proteasome system might afford clinical benefits.