# A shift in the cellular redox state redirects aspartate for export under glucose deprivation

## TL;DR

Cancer and normal lung cells release more aspartate when glucose is scarce, due to changes in a key metabolic pathway.

## Contribution

The study reveals a novel metabolic adaptation involving aspartate export under glucose deprivation in lung cells.

## Key findings

- Low glucose increases aspartate synthesis and export in lung cancer and normal cells.
- Aspartate export is reduced under hypoxia and suppressed by knocking out GOT2.
- Restoring NADH reverses aspartate synthesis under low glucose conditions.

## Abstract

Glucose is an important fuel in cancer cells, however, its availability may be limited in solid tumors. Cell-autonomous, metabolic adaptations of cancer cells and non-malignant cells to glucose deprivation are still incompletely understood.

Here, we addressed the changes in central carbon metabolism in lung cancer cells and normal lung cells facing glucose limitation using stable isotopic labeling followed by nuclear magnetic resonance spectroscopy and mass spectrometry.

Elevated levels and the release of newly synthesized aspartate were among the most prominent changes in low compared to high glucose conditions. The low glucose-induced export of aspartate occurred in different lung cancer cell lines, but also bronchial epithelial cells and cancer-associated fibroblasts. It was accompanied by a reduced use of aspartate in purine synthesis and suppressed by hypoxia. A knockout of the malate-aspartate shuttle (MAS) enzyme mitochondrial aspartate aminotransferase (GOT2) decreased aspartate release. Low glucose conditions diminished reduced nicotinamide adenine dinucleotide (NADH) and restoring NADH reversed aspartate synthesis, suggesting that the distal, NADH-dependent arm of the MAS is compromised under glucose deprivation.

Cells accumulate and release aspartate, a biosynthetic precursor and signaling molecule, under low glucose conditions, largely due to a truncated MAS, as part of their adaptive metabolic response.

The online version contains supplementary material available at 10.1186/s40170-026-00420-x.