After anoxia has occurred, what causes a cell (say a brain cell) to die? It seems that if the problem is simply a lack of oxygen, a few rescue breaths should fix it, like refueling a car that has run out of gas. What causes necrosis to be permanent?
The pathway that links energy failure and one form of cell death, necrosis, is not fully understood, and many biochemical events are likely involved. However, scientists have revealed one pivotal factor in this process, calcium. During evolution, the calcium ion (Ca2+) has been adopted by cellular organisms as a messenger to enable intracellular molecules to communicate with the external world.
While in the resting state, the cell maintains an extremely low free Ca2+ concentration (~0.1 μM) within its membrane, whereas the Ca2+ concentration outside its membrane, in the extracellular matrix, is ~1 mM, that is, 10,000-fold higher! This difference is achieved by energy-consuming pumps on the cell membrane, which pump Ca2+ from inside to outside against its concentration gradient. Under certain stimulations, specific membrane channels will open to allow Ca2+ to flow into the cell. Ca2+ can bind to many proteins and, in turn, modulates their biochemical reactivity. In the event of energy failure, the cell is no longer able to maintain its intracellular Ca2+ concentration. As a result, Ca2+ will accumulate in the cell and critical aspects of the cell’s biochemical system will become unregulated.
One catastrophic event occurs after intracellular Ca2+ accumulation takes place in mitochondria, the center for energy production and control of death in the cell. Mitochondria with high levels of Ca2+ will release a protein, called cytochrome-c, which is a common trigger for several types of “death pathways”, including necrosis and apoptosis (1).
Almost all types of cells are susceptible to calcium toxicity, with neurons having some additional weak points. As a computational device, the neuron functions through electrical activity. In the resting state, the neuron maintains a difference in electrical potential across its membrane, called resting membrane potential. Resting membrane potential is primarily maintained by an enzyme called Na+/K+-ATPase, which consumes energy to pump charged ions in and out (2). Many neuronal proteins have voltage sensors, so they are able to respond to the membrane potential change. During hypoxia, membrane potential quickly breaks down, causing voltage-sensitive proteins to be out of control, which eventually leads to cell death.
1. Niquet, J., Baldwin, R. A., Allen, S. G., Fujikawa, D. G., and Wasterlain, C. G. 2003. Hypoxic neuronal necrosis: Protein synthesis-independent activation of a cell death program. Proceedings of the National Academy of Sciences of the United States of America, 100(5):2825–2830.