A molecular geneticist at Montana State University has uncovered a previously unknown survival mechanism that allows mammalian cells to produce the amino acid cysteine even when the cellular systems normally responsible for supplying it stop working. Scientists once thought this kind of survival was impossible. The finding, published in Nature Chemical Biology, could eventually point researchers toward new ways to make some cancers more vulnerable to treatment.
"All cells need a constant supply of an amino acid called cysteine in order to stay alive," said the paper's lead author Ed Schmidt, a professor of genetics and development in the Department of Microbiology and Cell Biology in MSU's College of Agriculture. "Yet cysteine is not available outside of the cells." Cysteine performs several essential jobs inside cells. It is used to make proteins, helps cells protect themselves from damage and contributes to the formation of disulfide bonds.
These bonds help stabilize proteins and maintain their three dimensional structures. For decades, researchers believed that cells could not simply obtain cysteine from their surroundings. Instead, they must generate it internally by breaking apart cystine, an oxidized form of cysteine.
Cells normally accomplish this through what is known as a disulfide reductase system. Scientists had long assumed that having at least one functioning version of this system was essential for cellular life. "Scientists long believed this process was absolutely essential for all living cells," Schmidt said.
"However, we have discovered a previously unknown system in mammalian cells that can take over when the main systems fail." The discovery unfolded in three stages over nine years. Schmidt said the first major clue appeared in 2014, when a colony of genetically engineered mice survived under conditions that, according to scientific understanding at the time, should have been fatal. The mice lacked any known mechanism for converting cystine into the cysteine their cells required.
"This was supposed to be impossible," he said. "No living organism or cell had ever been found that could live without having a functioning disulfide reductase system." The finding was not the result of an accidental observation. Schmidt had previously engineered mice whose liver cells separately lacked one or the other of the two main disulfide reductases.
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