mTOR on the move
Location-specific functions and regulation of mTORC1 in cells
Eating less, intermittent fasting, anti-ageing drugs such as rapamycin - there is a lot of public advice on preventing age-related diseases. A central regulator that appears to be linked to all these measures is a protein complex called mTORC1 that functions in our cells both as a sensor of nutrient availability and as a controller of most cellular functions. A research group at the Max Planck Institute for Biology of Ageing in Cologne has now shown for the first time that mTORC1 functions differently at different locations inside cells. These new findings broaden our understanding of how mTORC1 is activated by nutrients and may help to develop new, more-targeted therapies against ageing and age-associated diseases.
The mTOR complex 1 (mechanistic Target of Rapamycin complex 1, in short ‘mTORC1’) is the central component of a protein network that senses whether a cell has access to sufficient nutrients. Therefore, it ensures that a cell grows only when nutrients are abundant and all other conditions are optimal. Because mTORC1 controls virtually all cellular processes, its activity is commonly found dysregulated in most human diseases and in ageing.
Cells take up nutrients like amino acids from their environment (exogenous amino acids), or they break down cellular material that is damaged or no longer needed inside vacuolar organelles called lysosomes. These ‘recycled’ nutrients (endogenous amino acids) are then released to the rest of the cell and reused as building blocks or energy sources. Despite intensive research for more than 15 years, how and where nutrients activate mTORC1, and how this complex controls cellular functions that take place at various locations inside a cell remained enigmatic. In fact, the widely accepted model in the field suggested that mTORC1 is activated by exogenous amino acids exclusively on lysosomes, while it becomes inactive when it leaves the surface of these organelles.
"Although this model sufficiently explains how mTORC1 is activated on lysosomes, at the same time it raises a number of outstanding questions: For instance, if mTORC1 is active only when it sits on lysosomes, how does it act on its various targets most of which localize at different places inside a cell? Also, conceptually, why would cells have developed a molecular machinery to sense exogenous amino acids on the surface of organelles like lysosomes?" says Constantinos Demetriades, who led the study.
Hit the road, mTOR!
The Max Planck researchers have now shown that active mTORC1 is present not only on lysosomes, but also at many other locations in a cell, such as the cytoplasm and the Golgi apparatus. At each of these places, mTORC1 acts on its different substrates to control distinct cellular functions. Furthermore, while lysosomal mTORC1 is activated primarily by endogenous amino acids that are generated inside these organelles, cytoplasmic mTORC1 senses amino acids that come from the outside.
In the context of an independent study, the researchers discovered that these are not independent pools of mTORC1 that act at each location inside cells. Instead, they are likely the same complexes that shuttle between lysosomes and the cytoplasm. More specifically, the researchers demonstrated that mTORC1 complexes that are activated on the lysosomal surface regulate their own release to meet their other targets elsewhere. Therefore, the intrinsic activity of mTORC1 is another important factor that determines where it localizes and where it acts inside cells.
“Our studies suggest that, similarly to the protein network that regulates mTORC1 on lysosomes and was put together over the past 15 years, there must exist an additional signaling network that allows cells to sense the availability of exogenous amino acids in the cytoplasm or elsewhere. Therefore, our work not only provides answers to several previously unanswered questions in the field, but it also opens a whole new world to discover in nutrient sensing and mTORC1 biology,” says Demetriades.
Implications for Rapamycin treatments
“Another potential implication of our recent findings is that rapamycin, by influencing the localization of mTORC1 inside cells, it also differentially affects how mTORC1 acts on its different targets on lysosomes and elsewhere. One day, we may be able to develop more targeted drugs that specifically inhibit mTORC1 at certain locations inside cells and thus towards certain cellular functions, while leaving others unaffected", Demetriades adds.
