PLA2 (right) shrinks nuclei during hypoxic death.

During heart disease and stroke, cells deprived of oxygen often die in a way that is distinct from caspase-dependent apoptosis. On page 1219, Shinzawa and Tsujimoto provide a first look at the molecular basis of this poorly understood process, showing that a phospholipase A2 (PLA2) enzyme causes the characteristic nuclear shrinkage that accompanies hypoxic cell death.

Using a novel permeabilized cell assay, the authors purified a protein that can cause nuclear shrinkage and identified it as PLA2. Inhibitor studies confirmed that PLA2 is essential for nuclear shrinkage in caspase-independent hypoxic cell death. In hypoxic cells, PLA2 activity increases and the calcium-independent form of the enzyme accumulates in the nucleus. Blocking calcium-independent PLA2 activity prevents both nuclear shrinkage and hypoxic cell death.

An increase in PLA2 activity leads to the cleavage of nuclear lamins, which could explain how it causes nuclear shrinkage. Since PLA2 cleaves phospholipids, it could also contribute to cell death by disrupting mitochondrial and plasma membranes, processes the authors now hope to study biochemically. The identification of PLA2 as an important mediator of caspase-independent death should also help uncover additional components of the pathway, such as the regulators of PLA2 activity and translocation. ▪