Death and the shrinking nucleus

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. ▪