Location matters: How one fat molecule can help trigger both cell limbo and cell death

BUFFALO, N.Y. — When cells experience enough chronic stress, they can stop dividing permanently. In this state of cellular limbo, known as replicative senescence, cells remain alive but no longer proliferate.

Pinpointing the stressors that help trigger or accelerate replicative senescence has proven difficult. 

Now, in a study published today (March 30) in Cell Chemical Biology, University at Buffalo scientists have shed light on one such stressor — showing that an impaired transport protein and a buildup of lipids known as ceramides can help lock cells into replicative senescence. 

Ceramides, a group of fat molecules, are produced inside cells’ endoplasmic reticulum (ER) and transported by the ceramide transfer protein to the cell’s Golgi complex. There, they are converted into another class of lipids known as sphingomyelin. 

However, during replicative senescence, the researchers found that this transport process becomes impaired, causing ceramides to accumulate inside the ER and trigger a stress response.

“It’s as if a delivery route inside the cell becomes blocked, preventing ceramides from reaching their proper destination,” says the study’s corresponding author, G. Ekin Atilla-Gokcumen, PhD, Dr. Marjorie E. Winkler Distinguished Professor and associate chair in the UB Department of Chemistry. “When these lipid molecules can’t be transported to the Golgi for processing, they begin to accumulate where they were made, inside the endoplasmic reticulum. That buildup appears to trigger stress signals that can ultimately push the cell to stop dividing.”

Ceramides are also involved in another cellular process — apoptosis, or programmed cell death. During apoptosis, ceramides build up at the mitochondria and weaken mitochondrial membranes. It’s a fatal wound that the cell cannot recover from.

So Atilla-Gokcumen’s team was interested when they first observed ceramides also accumulating in cells during replicative senescence.

“Ceramides are well known for accumulating at the mitochondria during apoptosis, where they help drive cell death,” says the study’s first author, Shweta Chitkara, a medicinal chemistry PhD student in Atilla-Gokcumen’s lab. “So when we saw ceramides building up in senescent cells, cells that are alive but no longer dividing, we had to ask: If they’re not killing the cell, what are they doing?”

The team took normal functioning cells and inhibited several enzymes key for ceramide production and metabolism. They wanted to see whether shutting any of them off led to replicative senescence.

This experiment eventually yielded a culprit: the ceramide transfer protein. From this, the researchers concluded that the transport protein becomes impaired during replicative senescence, preventing ceramides from reaching the Golgi and instead causing them to back up inside the ER. 

The disruption appears to trigger ER stress that can ultimately push the cell into replicative senescence.

“So it appears that ceramide is one molecule doing very different things, depending on whether a cell is reaching the end of its life or just the end of its proliferative capacity,” Atilla-Gokcumen says. “Ceramides are essential to cell function, but only at the right levels and in the right location, otherwise, you can end up with either cell death or cellular limbo.”

Replicative senescence protects against cancer by halting damaged cells, but as senescent cells accumulate, they may contribute to tissue decline and aging-related disease.

The study raises a key question: Is disrupted ceramide transport an intentional biological mechanism that locks cells into senescence, or is it a breakdown that occurs as cells age? If faulty lipid trafficking turns out to be a driver of aging-related dysfunction, restoring that transport pathway could offer a strategy to rebalance lipid organization and potentially reverse some age-associated cellular abnormalities.

“We’ve shown that interfering with this pathway is enough to induce senescence,” Atilla-Gokcumen says. “Understanding whether correcting that disruption can restore healthier cellular function is an exciting direction for future research.”

The study was co-authored by Paras Prasad, PhD, SUNY Distinguished Professor in the UB departments of chemistry, physics, medicine and electrical engineering. Other co-authors include Artem Pliss, PhD, a former UB research associate professor and now assistant professor at the D’Youville University School of Pharmacy; former UB medicinal chemistry student Natasha Gozali; and Mengru Li and Yasemin Sancak, PhD, of the University of Washington. 

The work was supported by the National Science Foundation.