Death by necrosis. Uncontrollable catastrophe, or is there order behind the chaos?

Abstract

Cells suffer necrotic death when exposed to extreme environmental conditions, adverse and excessive stimuli, or when deleterious mutations are encoded in their genetic material. Unlike apoptosis, which involves a highly regulated and elaborate network of biochemical events and cascades, necrosis has been considered generally to be a chaotic decadence process that effects the inexorable demise of cells otherwise not destined to die. This grim prospect is now slowly being overturned, mostly by exciting new findings in two simple model organisms, Caenorhabditis elegans and Drosophila melanogaster. Despite the wide spectrum of necrosis-initiating conditions, evidence is accumulating that execution of necrotic or neurodegenerative cell death may be carried out by a finite common set of mechanisms.

Fig. 1. Necrotic cell death in C. elegans. The most prominent morphological characteristic of necrosis is the outstretched swelling of the cell to several times its normal diameter, which is manifested by a hollow, vacuole-like appearance under the optic microscope. For example, a dying PVM (posterior ventral microtubule) touch receptor is shown in (A) by a red arrow. This neuron is expressing a toxic variant of the degenerin MEC-4 (mechanosensory) protein that induces necrosis. The nucleus follows the cellular expansion (A; blue arrow). Healthy cells are indicated by green arrows for comparison (B). In sharp contrast, apoptosis, which normally occurs during nematode development, generates retractile cell corpses, compact in size, with a characteristic button-like appearance (C; red arrow). Under the electron microscope, the same degenerating neuron exhibits dark, electron-dense formations, most likely originating from plasma membrane-internalized material, arranged in onion-like concentric circles (D; arrowheads). At later stages of degeneration, the cytoplasm of the dying cell appears extensively depredated and fragmented. A normal neuron is shown in (E) by a green arrow. (Reproduced in part with permission from Hall et al., 1997.)

Fig. 2. A likely death scenario. Many diverse initiating conditions that trigger necrosis (such as hyperactive ion channels and Gα_s proteins, and protein aggregates formed in cases of neurodegenerative diseases) may provoke a net increase in the cytoplasmic calcium concentration ([Ca⁺⁺]_i), either by stimulating uptake of extracellular calcium or by facilitating the release of calcium stores from the endoplasmic reticulum. Calcium could, in turn, signal the mobilization of executioner cathepsin proteases and other hydrolases through calpain activation. Calpains have also been implicated in the activation of pro-apoptotic caspase proteases (for a review, see Leist and Jaattela, 2001).

Nektarios Tavernarakis & Popi Syntichaki