Scientists have identified a previously unknown route for cellular fuel delivery, a finding that could shed light on the process of aging and the chronic diseases that often accompany it.
With age, cells gradually lose their ability to take in and process fuel. A cell that can't fill its fuel tank, so to speak, can't perform its proper functions. Researchers are interested in finding ways to boost the energy supply of aging cells in an effort to stave off the detrimental effects of the inevitable passage of time.
A key element of any cell's fuel supply chain is a molecule called nicotinamide adenine dinucleotide (NAD). Past work has shown that NAD levels in tissues throughout the body decrease with age. One way cells manufacture NAD begins with a precursor molecule called nicotinamide mononucleotide (NMN), which is found naturally in foods such as edamame, broccoli, cabbage, cucumber and avocado. But how NMN gets into cells to be processed into NAD has long been a mystery.
In a new study, scientists have identified a protein responsible for transporting NMN directly into cells, where it can be used for cellular fuel production. Not only does this protein move NMN into cells, it does so rapidly.
The study is published in the inaugural issue of the journal Nature Metabolism. The team long suspected there was a direct route for NMN to get into cells, simply because they had measured the speed with which NMN made the journey from the gut into the bloodstream and then into tissues throughout the body. In mice, that journey happens in a matter of minutes. The researchers felt there wasn't time for complex biochemical reactions that might convert NMN into another form that could be taken up by cells.
"To achieve such fast uptake of NMN into the tissues, we speculated that there must be a specific NMN transporter that moves NMN directly into cells, even though no one had ever seen such a thing," the author said.
The researchers conducted multiple experiments in cells and mice, identifying and then verifying that a protein called Slc12a8 is in fact the mystery transporter. The researchers also showed that Slc12a8 requires the presence of sodium ions to transport NMN into cells.
The scientists further showed, intriguingly, that cells dial up the expression of the Slc12a8 gene when NAD levels fall. When the authors deliberately lowered NAD levels inside cells and then gave NMN to compensate, the resulting NAD manufactured in the cell overshot the amount that was expecting to see. This suggested that cells don't just passively accept loss of NAD; they work to maintain their fuel supply by increasing amounts of the NMN transporter, thereby increasing their capacity to bring the raw materials required to make NAD into the cell. So aging cells can, to a degree, compensate for a depleted fuel supply. When NAD inside the cell drops, cells make more NMN transporters, increasing the amount of NMN they can bring inside.
The authors pointed to the importance of the interaction of NMN and its transporter. It may not be enough, for example, to give NMN if the transporter is not working well. They see a role for both supplementing NMN and enhancing the function of Slc12a8 -- the NMN transporter -- in therapies that might help maintain cellular energy levels with age.
Indeed, past work in the lab has shown that giving NMN to older mice has beneficial effects on metabolism throughout the body, including positive effects in skeletal muscle, liver function, bone density, eye function, insulin sensitivity, immune function, body weight and activity levels. They also found that the benefits of supplementing NMN were seen only in older mice. Young, healthy mice likely have no trouble manufacturing sufficient NAD.
"What may be important in a future strategy is the combination of giving NMN along with stimulating the transport of NMN into cells," the senior author said. "With aging, we see a bottleneck in NAD production. The body loses its ability to manufacture NAD over time. At the same time, it seems to begin burning more NAD, likely due to chronic inflammation. If we can give NMN and aid its transport into cells, that may be a way to bypass the bottleneck."
With this in mind, the lab already has identified small molecules that enhance the function of the NMN transporter. This technology has been licensed to a company that is working on new therapies targeting the chronic diseases of aging.
https://medicine.wustl.edu/news/scientists-identify-new-fuel-delivery-route-for-cells/
https://www.nature.com/articles/s42255-018-0009-4
Latest News
Immune cells identified as…
By newseditor
Posted 28 Mar
TB blood test which could d…
By newseditor
Posted 27 Mar
Propionate supplementation…
By newseditor
Posted 27 Mar
Role of human Kallistatin i…
By newseditor
Posted 26 Mar
Addressing both flu and COV…
By newseditor
Posted 26 Mar
Other Top Stories
Social trauma activates brain circuit to block social reward and pr…
Read more
An alternative splicing modulator decreases mutant HTT in Huntingto…
Read more
Changing the intrinsic behavior of neurons
Read more
How neurons respond to aged-related iron accumulation
Read more
Sleep signaling pathway in brain cells identified!
Read more
Protocols
All-optical presynaptic pla…
By newseditor
Posted 23 Mar
Epigenomic tomography for p…
By newseditor
Posted 20 Mar
A mouse DRG genetic toolkit…
By newseditor
Posted 17 Mar
An optogenetic method for t…
By newseditor
Posted 13 Mar
Profiling native pulmonary…
By newseditor
Posted 08 Mar
Publications
BHLHE40/41 regulate microgl…
By newseditor
Posted 28 Mar
Balancing neuronal activity…
By newseditor
Posted 28 Mar
OSBP-mediated PI(4)P-choles…
By newseditor
Posted 28 Mar
Integrated plasma proteomic…
By newseditor
Posted 27 Mar
APP antisense oligonucleoti…
By newseditor
Posted 27 Mar
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar