When human cells lack oxygen, they must react. Without oxygen, the metabolism can hardly generate energy, and many vital processes begin to falter. A research team from Bielefeld University, together with international partners, has discovered how cells can save energy in this situation: they deliberately slow down the so-called secretory pathway—the transport route through which cells release substances such as proteins to the outside or forward them to other cellular compartments. The study has now been published in the journal PNAS.

The researchers show that the protein NDRG3 plays a central role in this adaptation. NDRG3 acts as a sensor for the metabolic product lactate, which accumulates during oxygen deficiency (hypoxia). The protein intervenes in the transport process between two organelles, the endoplasmic reticulum (ER) and the Golgi apparatus. These structures function like the cell’s production and shipping departments: proteins are produced in the ER and further processed and distributed in the Golgi apparatus.

“We were able to show that NDRG3 specifically slows down transport between the ER and Golgi during periods of oxygen shortage,” explains Professor Michael Schwake, last author of the study. “This allows the cell to save energy and avoid unnecessary activity at a time when it is operating in low-power mode.”

A molecular switch that saves energy

In detail, the researchers found that NDRG3 binds to lactate—the metabolic byproduct that accumulates during oxygen deficiency—and, once “lactate-loaded,” can interact with a specific form of syntaxin-5. This protein is part of a so-called SNARE complex, a molecular membrane fusion system that shuttles small vesicles containing transport materials from one area of the cell to another. By binding to syntaxin-5, NDRG3 intentionally disrupts this process and ensures that transport between the ER and Golgi slows down

If NDRG3 is absent, this braking mechanism fails: cells lacking the protein continue transport even when oxygen is scarce. These findings thus provide a new mechanistic link between oxygen deficiency and the regulation of cellular metabolism.

New insights into disease mechanisms

Understanding these processes is not only relevant for cell biology. “Some diseases, such as muscle disorders and epilepsies, are linked to disruptions in precisely these transport pathways,” says Pia Ferle. “Our findings could therefore, in the long term, help explain why such diseases arise on a molecular level and how they might be treated more effectively.”

The study brings together two previously separate research areas: the cellular response to oxygen deficiency and the resulting increase in lactate, and the regulation of protein transport within the cell. It demonstrates how closely these processes are interconnected and how precisely cells can respond to changing environmental conditions.

Alongside Professor Schwake’s team, researchers from the United States were also involved in the study. The Bielefeld University team led the project and analyzed the molecular mechanisms in detail.