The transport of nutrients to our cells heavily relies on proteins in the cell membrane that ferry them across. If this system fails, it can lead to a range of health issues, from rare diseases to cancer. Understanding how metabolites enter cells could provide solutions for diseases linked to metabolite transport.
However, matching the carrier proteins to their specific nutrients has been challenging, with 30% still unaccounted for. A recent study published in Cell Metabolism has identified the protein responsible for transporting choline into cells. This discovery may have immediate implications for patients with posterior column ataxia with retinitis pigmentosa (PCARP), a disease caused by a mutation in this transporter protein.
Supplemental choline is easily available, and the study’s findings could be applied in a clinical setting. Additionally, the discovery may pave the way for further breakthroughs in understanding other transport proteins and diseases related to their dysfunction. By identifying orphan transport proteins systematically, we can solve mysteries in human biology and health. This study serves as a proof of concept for this approach.
A metabolite in a haystack
Scientists are still uncertain about how many of the approximately 5,000 different metabolites in human blood enter cells. To shed light on the matter, Kivanc Birsoy, Timothy Kenny, and their team embarked on a comprehensive investigation of transport proteins. They sifted through numerous studies linking transporters and metabolites in the human genome and found a strong association between choline and the membrane transport protein FLVCR1.
While multiple transport proteins were linked to specific metabolites, the team focused on choline due to its crucial role in cell membranes and neurotransmitters, and its deficiency’s association with several diseases such as fetal alcohol spectrum disorders, neurodegeneration, liver disease, and some cancers.
The link between FLVCR1 mutations and PCARP, which leads to muscle weakness, vision problems, and difficulties with spatial orientation, was an essential discovery, highlighting the possible implications of this pairing.
Confirming choline
To confirm that FLVCR1 is the transporter responsible for choline transportation, Birsoy and his team carried out a series of experiments. Their findings showed that mice lacking FLVCR1 die in utero, but can live longer if given choline supplements. They also discovered that human cells without the FLVCR1 gene are not only choline deficient, but also have their metabolism corrected when the equivalent gene in flies is present. These results indicate that the FLVCR1 gene is fundamental to life.
The team’s experiment with mouse embryos also suggests that mutations in FLVCR1 may be treatable with choline supplements. This finding could be relevant for PCARP patients who have a deficiency in choline, and choline supplements could be an effective therapy for them.
The Birsoy lab plans to apply the method outlined in this study to uncover more mysterious links between metabolites and transporters. The identification of such transporters is crucial as they are associated with many diseases and drug targets. “We have now developed an important strategy to achieve this,” Birsoy says.
Source: Rockefeller University