Cells have developed mechanisms to detoxify ROS and to repair oxidative damage,
but this can only reduce, not completely prevent, fatal cell damage. Most damaged
cells will continue to metabolize for some time, even when they have lost the ability
to proliferate. A rapid, active suicide of these cells would spare metabolic energy for
neighboring cells, which, even in the case of unicellular organisms, are mostly clonal
relatives, genetically identical to the damaged cell. That way, suicide of a unicellular
organism could provide an evolutionary advantage for its genome.
Higher eukaryotes evaluate cell damage (via the p53 system) to decide whether
suicide is advantageous. Before development of such a complex system, chemical
reactivity of ROS themselves may have been used to trigger cellular suicide.
To induce cell death in situations without external oxygen stress, cells developed
mechanisms to produce these signals autonomously. Such a suicide scenario has been
described by Longo et al. (1997), who observed that stationary cells of S. cerevisiae
survive for long periods in pure water but quickly lose viability in nutrient-depleted
synthetic media. Bcl-2 delays the loss of viability. These cells accumulate ROS and
die with an apoptotic phenotype (unpublished results). The source of the ROS is yet
unidentified. As oxygen radicals are normal byproducts of respiration, a specific
modulation of the respiratory chain may have been developed to increase the output
of ROS as needed. Release of cytochrome c leads to an accumulation of reduced
ubiquinone, increasing production of superoxide via the bc1 complex (Luetjens et
al., 2000). During a further refinement in the regulation of apoptosis, released
cytochrome c itself became used as an apoptotic signal, perhaps in order to make the
regulatory cascade less dependent on the redox state of the cell. With the development
of multicellular organisms, a more flexible regulation of apoptosis became necessary,
including responses to various external signals, resulting in additional regulatory steps
upstream, downstream, or instead of ROS.
7.
Apoptosis and aging in yeastS.cerevisiae proliferates by budding. A ‘mother cell’ produces a bud that grows into
a’daughter cell’, leaving a circular ‘bud scar’ on the cell wall of the mother cell. The
number of scars therefore indicates the ‘replicative age’ of the respective mother cell.
Yeast mother cell-specific aging has been intensively researched and reviewed
(Jazwinski, 1999; Johnson, F.B. et al., 1999; Costa and Moradas-Ferreira, 2001) in
recent years. Similarities of morphologic and physiologic changes make yeast a simple
model system for cellular and, perhaps, also organismic aging.
Old yeast cells (mother cells which have produced more than 30 daughter cells)
are much larger than young ‘virgin’ cells (that have budded no daughter cells yet);
their cell cycle as well as protein synthesis is slowed down, and the cell surface develops
a loose and wrinkled appearance. The median life span of most laboratory strains of
S. cerevisiae is about 25–35 generations or about three days. Nestelbacher et al. (2000)
have shown that genetic and environmental changes that increase the burden of ROS
on yeast cells result in a shortening of the life span of mother cells. Deletion of yeast
REGULATORS AND APPLICATIONS OF YEAST APOPTOSIS 147