Previously uncharacterized proteins regulate the mitochondrial NAD transporter

For their growth, cells need various nutrients and vitamins. So-called solute carriers (SLCs), proteins capable of transporting these substances across the boundaries of cell membranes, play a central role in metabolism.

Scientists from Giulio Superti-Furga’s research group at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences have now discovered that the previously uncharacterized protein SLC25A51 acts as a transporter in mitochondria for coenzyme NAD.

This molecule has already been associated with numerous physiological and pathological processes such as aging, neurological diseases and the metabolism of cancer cells. Therefore, the results of this study not only open up new possibilities for studying the biological role of NAD, but also potentially provide the basis for new therapeutic approaches. The work has now been published in the journal Nature Communications.

Solute transporters (SLC) are proteins that act as transporters and allow the entry and exit of nutrients and waste products into and from the cell and its organelles. Many of these carrier proteins are still relatively poorly studied, and the question of how certain nutrients enter and leave cells often remains unanswered.

So far it has not yet been clarified how mitochondria have access to an important cofactor of our metabolism, the so-called NAD (nicotinamide adenine dinucleotide). In the scientific literature, there were only references to mitochondrial NAD transporters in plants and yeast.

The lead author Enrico Girardi and the research group of the Scientific Director of the CeMM Giulio Superti-Furga, in collaboration with scientists from the University of Bari (Italy), have now identified the protein responsible for the important transport of NAD in mitochondria: SLC25A51 .

Measurement of nutrient pathways has provided evidence

For their studies, the scientists used a specially created cell line library, which allows them to study the pairwise genetic interactions of two SLCs. Their genes are deactivated both individually and in pairs; the effects of these interventions on cell growth can then be measured. Among the large number of measured interactions related to the combination, some stood out around the previously uncharacterized gene SLC25A51.

The other interacting SLCs carry various nutrients, but all of them may be associated with NAD via known metabolic processes.

“By accurately quantitatively measuring certain nutrients in the cells, we found that the presence of SLC25A51 correlated with the amount of NAD and that cells lacking SLC25A51 had extremely low levels of this molecule in their mitochondria,” explains senior author Giulio Superti-Furga. .

“In our study, we also showed that the already known NAD transporter in yeast and SLC25A51 play a similar role in the human cell.”

Important part of the scientific puzzle

The question of the existence of a mitochondrial NAD transporter in humans has long been debated. Giulio Superti-Furga also explains:

The results of our research, which have also been confirmed in two other independent studies from US laboratories, provide an important answer to this question and open the opportunity to influence the NAD content in this key organelle. NAD is associated with many physiological and pathological processes such as aging, neurological diseases and the metabolism of cancer cells. Our study therefore represents an important contribution to understanding the biological role of this molecule. At the same time, we also see the enormous therapeutic potential deriving from the possibility of a possible modulation of the NAD content in the mitochondria by the transporter SLC25A51 “.