Notes

AUTOPHAGIC CELL DEATH
The first description of lysosomes, and indeed the name, included the
assumption that the rupture of lysosomes was the common form of cell
death. This conclusion was apparently valid for the specific situation of
carbon tetrachloride toxicity in liver, in which the CCl4 could dissolve lysosomal and cell membranes, but it proved to be a simplistic interpretation of
most other cell deaths. Nevertheless, the discovery launched a wide-ranging
evaluation of lysosomal activity in cell death, an active field through the
1970s. These studies led to the conclusion that, in developmental cell deaths,
the pool of lysosomal enzymes may be expanded as cell death is activated
(Lockshin, 1969a; Lockshin and Williams, 1965d) or merely “activated” (formation of autophagic vacuoles rather than primary lysosomes—Helminen
and Ericsson, 1970). As interpreted today, the lysosomes detected are either
the lysosomes of phagocytic cells, or there is an expansion of the lysosomal
system driven primarily by the formation of autophagic vacuoles. As is
explained in the chapter by Bursch et al., autophagic vacuoles are most
clearly seen in large, postmitotic, sedentary cells. In these cells, the primary
consideration is the removal of large amounts of cytoplasm, and the destruction of DNA is not a high priority. Thus, the early activities are the lysosomal destruction of cytoplasm, with DNA degradation occurring very late or
not at all, and generally these deaths are not caspase-driven (see next
section). Much remains to be learned of autophagic cell death. For instance,
autophagy is often seen in atrophying cells, in which cytoplasm is reduced
and the cell may enter a quiescent state, but the nucleus and the cell survive.
The turning point or threshold is not well understood, although it may
follow a schematic as presented by Tolkovsky, Bampton, and Goemans.
Also, we know very little about the mechanisms by which the membranes
of the autophagic vacuoles are formed, how they encircle target organelles
or regions of cytoplasm, or how target organelles, such as mitochondria,
expose markers or signals that identify them as targets. Many of the components are being identified (Klionsky and Emr, 2000), but the transients and
control mechanisms remain to be explored.







NECROSIS
For a metazoan it is always preferable to control the death of cells, to contain
the escape of potentially destructive molecules such as proteases and inflammatory cytokinins as well as invasive organisms such as viruses. Apoptosis,
described below, contains the dying cell and avoids inflammation. Viruses,
on the other hand, typically attempt to avoid this effective virus-controlling
route. Their goal is not to lose their host cell or, if this is not an option, to
provoke lysis and an inflammatory response through which they can escape.
Therefore, viruses often have apoptosis-blocking mechanisms.
If the cell is very sick and cannot undergo apoptosis, it follows the route
of necrosis. Likewise, when a cell is suddenly confronted with a severe stress,
such as a sharp change in tonicity, ion concentration, or pH, of the extracellular medium; or if all energy resources are suddenly extinguished, as in an
infarct; if an increase or decrease of temperature makes the maintenance of
homeostasis impossible; or if the integrity of the cell or organelle membranes
is compromised by a solvent or physical disrupter of a membrane, the cell
will simply rupture. The typical sequence is that mitochondrial failure will
allow entrance of Ca++ into mitochondria, swelling and rupture of mitochondria, loss of ion pumps, followed by loss of osmotic control of the cell,
osmotic swelling and lysis of the cell, invasion of macrophages and inflammation, and removal of the debris. In electron microscope images, nucleoplasm and cytoplasm show disorganized precipitation of proteins, and there
is no evidence of any active response of the cell to any stage of this disintegration (Fig. 5). The process is not stepwise and may follow different sequences.