LONDON – Apoptosis is a well-known type of programmed cell death, but it's not the only way that cells can bring about their own death. There's also necroptosis – in which cells spectacularly burst and die, rather than withering away as in apoptosis.
Necroptosis has been the poor relation of apoptosis for a long time. Neglected by researchers, no one knew exactly how it occurred.
Now a new study has identified some of the key molecular events that led up to necroptosis, giving rise to hope that it may be possible to develop drugs to modulate this process.
Peter Vandenabeele, group leader at the research institute, VIB, and the University of Ghent in Belgium, told BioWorld Today, "We have found that the mechanism by which cells die by explosion during necroptosis involves the formation of pores in the cell membrane. Because this type of cell death is highly associated with induction of inflammation, if we can find ways to slow it down, we will also be able to retard or prevent the inflammation."
Vandenabeele and his collaborators report their findings in a June 4, 2014, paper in Cell Reports titled "MLKL Compromises Plasma Membrane Integrity by Binding to Phosphatidylinositol Phosphates." The first author is Yes Dondelinger.
Necroptosis is known to occur commonly in cells affected by lack of oxygen. In particular, it happens in conditions where cells have been starved of oxygenated blood and are then reperfused with oxygen-rich blood, as can happen in the brain following stroke, in the heart following myocardial infarction, or in a transplanted organ. It can also occur in the limbs or extremities in diseases where there is poor blood circulation, such as peripheral atherosclerosis and type 2 diabetes.
Research had established that a group of enzymes called the RIP kinases played a key role in regulating this type of cell death. Subsequent studies using animal models had shown that it was possible to block necroptosis by using molecules that could inhibit the RIP kinases. When researchers used this strategy in animal models of stroke, myocardial infarction or kidney transplant, they found that blocking necroptosis helped to preserve the function of the affected organs.
Vandenabeele's team had also previously studied an animal model of septic shock.
"We think that when the cells burst and release their contents, this creates a kind of sterile inflammation that provokes the production of cytokines and can lead to shock. In the animal model of septic shock, blocking the RIP kinases led to encouraging results," he explained.
A Chinese team led by Xiaodong Wang contributed a key piece of information in 2012. These researchers were able to show that a protein called MLKL was also important for the function of the RIP kinases in necroptosis.
The Belgian team therefore decided to conduct a structure/function analysis of MLKL in order to find out its mechanism of action.
"We found that there was an electrostatic attraction between the negatively charged phospholipids on the plasma membrane of the cell and positively charged amino acid residues on part of the MLKL molecule," Vandenabeele said. "This allows recruitment of MLKL to the membrane, where it forms pores in the plasma membrane. As a result, although it is not entirely clear yet how this happens, water enters the cell in an uncontrolled way and eventually causes it to burst."
The researchers believe that gaining detailed knowledge about how the MLKL proteins create the pores will make it possible to develop medication that will counter or tolerate cell death, by preventing or temporarily blocking this process.
"We want to work out the structure of the pores," Vandenabeele said. "We also want to identify small molecules that can prevent pore formation or can prevent the recruitment of MLKL to the membrane, with the aim of slowing down the cell death process and the inflammation associated with necroptosis."
Boosting necroptosis could also have its uses, he added. "You might want to induce necroptosis in cancer cells that have become resistant to chemotherapy, for example, or to resensitize cancer cells to enter the cell death pathway."