Why Cysteine Is Essential for Cell Survival

This discovery in natural chemical biology could ultimately help researchers identify new approaches for treating cancer.

“All cells require a constant supply of an amino acid called cysteine to stay alive,” said Ed Schmidt, lead author of the paper and professor of genetics and embryology in Montana State University’s Department of Microbiology and Cell Biology. “But cysteine is not available outside the cell.”

Cysteine performs several important functions within cells. It helps build proteins, protects cells from damage and contributes to the formation of disulfide bonds. These bonds stabilize proteins and help maintain their three-dimensional structures.

For decades, researchers believed that cells could not obtain cysteine from their surroundings. Instead, cells were thought to produce it internally by breaking down cystine, the oxidized form of cysteine.

Cells typically perform this process through a system known as the disulfide reductase system. Scientists have long believed that at least one functioning version of this system is essential for cellular life.

A Newly Discovered Backup System

“Scientists have long believed that this process is absolutely essential for all living cells,” Schmidt said. “But we have discovered that there is a previously unknown system inside mammalian cells that can take over when the primary system fails.”

The Mouse That Survived Against Expectations

The discovery developed over three stages during nine years of research.

Schmidt said the first major clue appeared in 2014, when a colony of genetically engineered mice survived conditions that should have been lethal according to the scientific understanding at the time. The mice lacked any known mechanism for converting cystine into the cysteine required by their cells.

“That shouldn’t have been possible,” he said. “No organism or cell has ever been discovered that can live without a functioning disulfide reductase system.”

The observation was the result of earlier experiments in which Schmidt engineered mice whose liver cells were individually deficient in one or the other of two major disulfide reductases.

The behavior of these animals led him to question whether the established assumptions about cellular survival were correct.

“Some of the physiological responses observed in the liver of each of these mouse strains suggested that the idea that cells cannot survive without at least one of these two reductases may not be correct,” he said. “I wanted to test this.”

How Mammalian Cells Obtain Cysteine Without the Usual Pathway

It took another seven years to identify the explanation.

Schmidt’s team collaborated with co-investigator Peter Nagy and his group at the Hungarian National Institute of Oncology in Budapest. Nagy’s team provided analytical capabilities that helped researchers determine how cells acquire cysteine from cystine despite lacking a functional disulfide reductase system.

The researchers discovered that mammalian cells have an alternative chemical pathway.

When the normal disulfide reductase pathway is unavailable, this backup mechanism cleaves adjacent carbon-sulfur bonds within cystine. The reaction liberates cysteine, making it available to the cell.

The pathway gives cells another way to obtain molecules essential for survival even after their well-known cellular machinery has failed.

An Ancient Defense Against Environmental Toxins

Schmidt said the backup system may have originally evolved as a defense against electrophilic toxins.

Many electrophilic toxins are organic molecules produced by organisms as chemical weapons against predators or competing organisms. By giving cells another way to withstand chemical stress, the newly identified pathway may have provided an evolutionary advantage to early multicellular organisms.

“The ability of our cells to survive, at least temporarily, without disulfide reductase likely evolved in our earliest multicellular ancestors as a mechanism by which these organisms could resist being killed by electrophilic toxins produced by what they ate or found in their environment,” Schmidt said.

Could the Pathway Help Cancer Cells Resist Treatment?

The mechanisms that protect healthy cells can also have unwanted effects.

Researchers suspect that some cancer cells may use this backup pathway to survive chemotherapy, radiation therapy and immunotherapy. Although these treatments are designed to damage or destroy cancer cells, cellular defense systems may help tumors withstand treatment-related stress.

“This same pathway that protects our cells from oxidants and toxins is also likely to protect cancer cells from treatments,” Schmidt said. “Now that we know they have this defense mechanism, we may be able to precisely turn it off in cancer as well, making them more susceptible to cancer treatment.”

If scientists can learn how to selectively interfere with the pathway inside tumors, the discovery could eventually provide another way to improve the effectiveness of existing cancer treatments.

Students Contributed to the Discovery

Several Montana State University students contributed to the research, including students who have since graduated.

Zoe Seaford and Sydney Austad were co-lead authors and worked as undergraduates in Schmidt’s laboratory. Martina Serrano Alvarez and Reid Noyd also participated as undergraduates, while Colin Miller contributed as a doctoral student.

Scientists and trainees from several other institutions also contributed to portions of the research.

“This scientific advance is redefining what we thought was possible and underscores the power of research to advance new approaches to cancer treatment,” said Sreekala Bajwa, dean of the College of Agriculture. “I salute Dr. Schmidt and his team for their outstanding work and for engaging students as true partners in research that impacts the world.”

Schmidt joined Montana State University in 1999. His research interests include gene regulation, cellular and organismal physiology, mouse genetics, embryology, biochemistry, metabolism and laboratory mice whose DNA has been genetically modified by inserting one or more genes from another organism into the mouse genome.