Apoptosis, or programmed cell death, is a process by which a cell
“commits suicide,” usually in response to damage or mutations that
irreversibly alter cell function. Although programmed cell death has
been well-described, it’s not known whether similar programmed death
phenomena occur in sub-cellular structures, such as mitochondria, or in
larger structures, such as organs or even entire organisms.
Mitochondria, the tiny cell parts that produce energy for the cell,
also generate free radicals such as superoxide. Normally, the
mitochondria detoxify these highly reactive and toxic byproducts by
means of antioxidant systems. If superoxide production increases to a
critical level, however, the antioxidant systems are overwhelmed and
cannot detoxify all of the superoxide. Without adequate defenses, the
mitochondria and other cell structures quickly fall victim to
superoxide’s destructive reactions.
Mitochondrial membranes are particularly susceptible to attack by
superoxide. Damage to these membranes makes it impossible for the
mitochondria to move vital substances back and forth through the
membranes. This means mitochondria are no longer able to take in the
substances needed for energy production and reparation of the
organelle. In particular, proteins produced in the cytosol cannot be
transported into the mitochondria.
This catastrophic sequence of events leads to mitochondrial suicide,
thus eliminating the defective mitochondria from the remaining normal
mitochondria of the cell. In some cases, however, mitochondria are
grouped closely together along filaments in a type of network
configuration. We predicted that reactive oxygen species would cause
decomposition of the entire mitochondrial network. To test this, we
added hydrogen peroxide (a toxic byproduct of superoxide reactions) to
monkey kidney cells that contained a mitochondrial network. Nothing
happened for about hour, but then in a matter of seconds the entire
mitochondrial network decomposed. Further studies indicated that later
the mitochondria had ruptured and leaked their contents into the
cytosol. We have termed this phenomenon of elimination of the
mitochondria “mitoptosis”.
Apoptosis often follows mitoptosis, but the two events can be
separated if signals from the dying mitochondria can be blocked before
they can trigger overall cell death. If the block is successful, the
cell will survive even though the mitochondria have been destroyed. In
a study evaluating separation of mitoptosis and apoptosis, more than
60% of the cells examined had no mitochondria, yet no abnormalities
occurred in the other parts of the cell. This indicates that mitoptosis
can exist in the absence of apoptosis.
Suicide pathways are not solely used in damage situations. They also
occur in normal development of embryo and in some cases are essential
for survival. For example, when mice lack a protein called “apoptosis
inducing factor,” the embryo dies in the eighth day of development—a
time when apoptosis of some embryonic cells normally occurs. Mouse
embryos lacking cytochrome c, another protein enzymes involved in
apoptosis, die after two weeks of development.
When one cell undergoes apoptosis, can it then somehow transmit an
apoptotic signal to neighboring cells? We have evidence that indicates
that it can. Apoptosis then spreads throughout a tissue or organ like
an infection. For example, when tumor cells are treated with tumor
necrosis factor, which causes cell death, one cell dies, then other
nearby cells start to die. This type of collective
apoptosis—disappearance of an organ—also occurs during development of
the embryo, when some organs normally disappear.
Phenoptosis, or elimination of an entire organism, can also occur,
at least in one-celled organisms. Whether this occurs in more complex
organisms has not been determined. However, the possibility leads to
speculation as to whether aging represents breakage of a complex system
or perhaps just phenoptosis.
It is interesting to consider the possibility that mitoptosis,
apoptosis and other programmed death phenomena are essential elements
of evolution used to select beneficial mutations and adaptations.
Perhaps programmed death is an evolutionary mechanism that uses
reactive oxygen species as a tool to accomplish this selection.
This research was funded by the Ludwig Institute For Cancer Research.
