Montana State Researchers Discover Backup Cellular Pathway for Cysteine Production, Opening New Avenues for Cancer Therapy
Key Insights
Montana State University scientists discovered a previously unknown backup system that allows mammalian cells to produce the essential amino acid cysteine when primary disulfide reductase systems fail.
The nine-year study, published in Nature Chemical Biology, overturns the long-held belief that cells cannot survive without functioning disulfide reductase systems.
The newly identified pathway chemically severs a carbon-sulfur bond in cystine to release cysteine, a mechanism that may have evolved to protect against electrophilic toxins.
A molecular geneticist at Montana State University has uncovered a cellular process long considered impossible: the ability of mammalian cells to produce the essential amino acid cysteine through a previously unknown backup mechanism when their primary systems fail. The discovery, published May 21 in Nature Chemical Biology, challenges decades of established scientific dogma and may ultimately lead to new strategies for sensitizing cancer (search) cells to existing therapies.
"All cells need a constant supply of an amino acid called cysteine in order to stay alive," said Ed Schmidt, the paper's lead author and a professor of genetics and development in the Department of Microbiology and Cell Biology at MSU's College of Agriculture. "Yet cysteine is not available outside of the cells."
A Fundamental Cellular Requirement
Cysteine plays an indispensable role in cellular survival, enabling protein synthesis, defending against oxidative damage, and facilitating the formation of disulfide bonds that stabilize proteins in their three-dimensional conformations. For decades, researchers have understood that cells cannot access cysteine from their external environment. Instead, they must generate it internally by chemically splitting an oxidized form called cystine through a process known as the disulfide reductase system.
"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."
A Nine-Year Journey to Discovery
The breakthrough unfolded across three stages over nearly a decade. The first pivotal moment came in 2014, when a colony of genetically engineered mice survived despite lacking any known system to convert cystine into cysteine.
"This was supposed to be impossible," Schmidt recalled. "No living organism or cell had ever been found that could live without having a functioning disulfide reductase system."
The finding was not accidental. Schmidt had already engineered mice to individually lack one or the other of the two primary disulfide reductases in the liver. "Some of the physiological responses we were seeing in the livers of each of those mouse lines suggested to me that the belief that no cell could live without having at least one of these two reductases might not be correct," he said. "I wanted to test this."
It took seven additional years for Schmidt and his team, in collaboration with Peter Nagy from the Hungarian National Institute of Oncology (search) in Budapest, to elucidate the underlying mechanism. The researchers determined that when cells cannot employ a disulfide reductase system to obtain cysteine, the backup system chemically severs an adjacent carbon-sulfur bond in cystine, ultimately releasing cysteine for cellular use.
Evolutionary Origins and Therapeutic Implications
Schmidt hypothesizes that this backup pathway evolved in early multicellular ancestors as a defense mechanism against electrophilic toxins — organic molecules produced by certain organisms to kill predators. "The ability of our cells to survive, at least for a time, without disulfide reductases, likely evolved in our earliest multicellular ancestors as a mechanism that allowed these organisms to resist being killed by electrophilic toxins made by the things they ate or the things found in their environment," he explained.
Critically, this same protective pathway may also confer a survival advantage to cancer (search) cells facing therapeutic assault. "This same pathway that protects our cells from oxidants or toxins also likely protects cancer cells from therapies," Schmidt noted. "Now that we know they have this defense mechanism, we might be able to precisely disable it in cancers, making them more susceptible to cancer therapies, as well."
The research team included several MSU students as co-authors, with co-first authors Zoe Seaford and Sydney Austad completing their contributions as undergraduate students in Schmidt's laboratory. Additional student co-authors included Martina Serrano Alvarez, Reed Noyd, and doctoral student Colin Miller, alongside collaborators from other institutions.
"This scientific breakthrough underscores the power of research to redefine what we thought was possible and advance new approaches to cancer (search) treatment," said Sreekala Bajwa, dean of the agricultural college. "I congratulate Dr. Schmidt and his team for their exceptional achievement and for engaging students as true partners in research that delivers global impact."