Don’t Forget to Take Your Vitamin K!
How vitamin K plays a role in preventing cell death
Background
What happens to cells when they are old, damaged or simply no longer needed? You have probably heard of apoptosis, programmed cell death, where a cell breaks down its contents and the remaining material is swallowed by phagocytic cells. Apoptosis can be bad if it happens when it’s not supposed to, e.g. if it is induced by a pathogen, but most of the time it is good for an organism. Think cleaning up old cells and materials that are no longer useful for the cell.
Ferroptosis, the subject of this paper, is programmed cell death that requires iron for its destruction mechanism (the prefix ferr- indicates involvement of iron). Ferroptosis uses the process of lipid peroxidation to destroy a cell. This is where radical species (very chemically reactive) are generated to degrade the lipid membrane. A free radical species can basically rip cellular components apart because it is so reactive.
Summary
Since ferroptosis can be a cause of organ damage, the researchers wanted to test the ability of vitamin K to make cells resist lipid peroxidation and therefore ferroptosis. The researchers tested three slightly different forms of vitamin K (phylloquinone, MK4 and menadione) but focused especially on MK4.
The first step for the researchers was deleting a gene for protein GPX4 in mice (the test subjects) because this protein protects cells against ferroptosis and they wanted to study vitamin K’s protective ability. The scientists performed a series of experiments to test vitamin K against ferroptosis and found that all three forms of vitamin K are anti-ferroptotic. Also, three forms of vitamin K can rescue cells even when ferroptosis-inducing agents are present (see figures 1a, 1b, 1c).
For the second part of the study the researchers focused on the mechanism of the vitamin K cycle. Vitamin K is chemically modified to create several different organic molecules which eventually go back to being vitamin K and thus form a cycle. Basically, the cycle is a series of oxidation/reduction reactions performed by different enzymes. In the first part of the cycle vitamin K is converted to VKH2 which can act as a radical-trapping agent (RTA) that prevents lipid peroxidation.
The vitamin K cycle is useful for the cell for several reasons, but here researchers focused on its role in warfarin poisoning. Warfarin is a blood thinner that can be used to treat blood clots. However, if too much is given it can completely prevent coagulation for long periods of time. This means a person could bleed out from even a small cut. Vitamin K has a role in blood clotting and warfarin works by inhibiting a protein in the cycle called vitamin K epoxide reductase (VKOR). If VKOR is not functional, the entire cycle stops and vitamin K cannot be regenerated.
The researchers found that warfarin poisoning can be stopped by adding a reductase protein called FSP1. The scientists used fluorescent tags to track lipid peroxidation when FSP1 was introduced. This protein is a reductase enzyme that is chemically similar to VKOR and can prevent lipid peroxidation. They induced warfarin poisoning in mice and found that FSP1 and high doses of vitamin K can be used to rescue cells from warfarin poisoning and stop the mice from dying.
To sum it all up, these scientists were looking for mechanisms to prevent harmful ferroptosis in cells. They found that vitamin K can rescue cells from ferroptosis (specifically caused by warfarin poisoning) if the vitamin K is given in large amounts. They found that the protein FSP1 can take the place of the VKOR protein (inhibited by warfarin) and continue the vitamin K cycle.
