Department of Bioenergetics, Belozersky Institute of Physico-Chemical Biology Lomonosov Moscow State University Moscow, Russia
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.