TALKING MOLECULES? THE CASE FOR mTOR
IS IT POSSIBLE that a molecule can converse like cells and organelles? It is not clear, but there is at least one candidate worth considering. A nutrient-sensing enzyme, called mTOR, has wide-ranging effects on cell processes related to growth. This molecule forms two large multiprotein complexes that receive messages about varied cellular activities and respond to all of them, simultaneously. These signals have wide-ranging repercussions for multiple illnesses, such as diabetes, cancer, seizures, and degenerative brain disease. Signals from the complexes also affect the global operation of the human brain related to sleep, appetite, circadian rhythms, and the clearing of misfolded proteins.
mTOR molecule. (Astrojan/Wikimedia Commons)
The history of research about this molecule began when a naturally derived antibiotic was discovered in the 1970s on Easter Island in the Pacific Ocean. The antibiotic was called rapamycin, from the island’s indigenous name, Rapa Nui. Rapamycin was produced by bacteria to stop fungal reproduction, but it also had multiple other effects. It was found to increase life span in animals, similar to the way calorie restriction does. As it did in fungi, rapamycin stopped particular human cells from growing, including B lymphocytes and some cancer cells. It inhibited the actions of T cells. Later, even more functions were discovered for rapamycin. Currently, it is used to suppress the immune system after transplants.
In trying to figure out how rapamycin works, researchers discovered a similar molecule that operates in somewhat the same way, but in competition with rapamycin. When a third molecule was found to be the target of both of these molecules, it was called the target of rapamycin, or TOR. Rapamycin, it appeared, turned a TOR switch on and off. Later, TOR was found in multiple species, and the version in mammals was named mTOR, for the mammalian target of rapamycin.
The mTOR molecule and its large complexes were found to consist of multiple sections, each related to important cellular pathways for cell growth, inflammation, cancer inhibition, and reproduction. Complexes contain receptors triggered by hormones, immune signals, growth factors, and nutrients. They sense levels of all sorts of molecules that are needed in the cell, including amino acids, lipids, oxygen, and high-energy phosphate molecules, such as adenosine triphosphate (ATP). Signals are then sent to regulate cell pathways for each type of molecule so that enough of these necessary cellular building blocks are available for every organelle.
mTOR PROTEIN COMPLEXES
mTOR is an enzyme that catalyzes multiple chemical reactions. It removes high-energy phosphate particles from one molecule and places them on another, causing changes in activity—one part of the molecule binds to the energy particle and another to mTOR protein complexes that are part of signaling cascades. In this way, mTOR triggers messages in pathways involving the altered molecules. What is surprising is how many different signals can be sent this way to influence cycles throughout the cell at the same time.
mTOR’s major focus is directing the two large multiprotein complexes that sense when there are enough nutrients for the cell to grow and divide. To regulate these global functions, mTOR stays in touch with the condition of multiple organelles. Both protein complexes are involved in multiple pathways and use various signals, often active at the same time in separate organelles with different, but interrelated, functions. With mTOR as the center, the two complexes work together to monitor information from inside and outside the cell. Together, they respond to the needs of the cell by altering basic metabolic cycles and triggering more energy and supplies when needed.
There are multiple ways the two complexes provide interrelated functions. For example, when receptors on the first complex pick up information about available proteins and RNA to produce proteins, mTOR is activated and sends back signals that regulate protein manufacturing, including stimulating and inhibiting actions of ribosomes and messenger RNAs.
Meanwhile, the second complex regulates the actions of the important protein actin, which forms scaffolds. With the amount of actin production directed by the first complex, signals from the second complex cause actin filaments to start constructing scaffolding in axons and dendrites, such as in response to neuroplasticity from learning. This occurs in many other cells as well but is easier to observe in neurons.
Working together, mTOR and the two complexes provide support for cell division, responses to low-oxygen conditions, and repair of damaged tissues. During cell division, activation of mTOR triggers production of key cellular ingredients, such as membranes, DNA, proteins, and organelles. Cancer cell signals try to keep this mTOR stimulation going nonstop, which can produce uncontrolled cell division. Unfortunately, mTOR-focused medications for cancer have been disappointing, because mTOR complexes affect so many pathways at once. Therefore, it is not yet possible to stop cancer’s uncontrolled reproduction without other unwanted consequences.
In situations of low oxygen and damaged tissues, mTOR signals stimulate alternative metabolic cycles to mitigate the need for oxygen, and they trigger stem cells to produce more blood vessel cells. They also trigger more tissue cells for rapid repair. However, overstimulation of stem cells by mTOR can cause them to lose the power to differentiate. This occurs during drawn-out infections and trauma in which gradual loss of stem cells increases signs of aging.
mTOR AND LYSOSOMES
mTOR works closely with lysosomes, vesicles that remove debris and recycle material for use throughout the cell. Both mTOR and lysosomes identify levels of material needed for the cell, and they both respond with signals to increase or decrease production via recycling. mTOR complexes often sit right on the lysosome’s outer membrane for this close cooperation. Lysosomes also engage in communication with multiple organelles related to responses to infection and production of energy particles. Mitochondria have recently been observed docking with lysosomes for conversations about energy, via special communication platforms in both organelles.
Collaboration between lysosomes and mTOR removes debris, including misfolded proteins, damaged organelles, and microbes. For this trash-disposal process, a series of large and small vesicles is built, with central coordination lodged in the largest lysosome vesicles, which have the ability to disassemble most types of molecules. Remarkably, lysosome vesicles are able to maintain an exact pH between 4.5 and 5 in their minuscule space, like the stomach is able to do. This highly acidic level of pH allows easier breakdown of large molecules by the lysosomes’ fifty unique enzymes.
mTOR signals are vital for the three distinct mechanisms that lysosomes use to gather damaged material. One mechanism for collecting debris involves surrounding impaired molecules with vesicles, which fuse with lysosomes. Lysosomes and mTOR send signals to the Golgi to produce membranes for debris-gathering vesicles. They can also stimulate vesicles that eject debris out of a cell. A second mechanism involves lysosomes that pick up debris directly through invaginations in their membranes. A third involves proteins in the endoplasmic reticulum that place tags on debris and then send the debris to the lysosomes, where multiple transporters are produced to bring these waste molecules inside.
Lysosomes and mTOR regulate each other’s activities with signals that stimulate and inhibit. When there is a problem getting the proper amount of nutrients for organelles, more recycling is triggered by mTOR signals. Signals cause increased breakdown of large molecules into constituent parts such as amino acids, nucleic acids, and simple fats and sugars. Signals also stimulate diverse lysosome sizes, which can vary as much as ten times, based on the types of materials they are working with—large proteins, nucleic acids, carbohydrates, and fats.
Lysosomes near a Golgi body. mTOR works closely with lysosomes, breaking down molecules to supply the amount of molecules needed for the cell. Electron micrograph. (Science Source/Science Source/Science Source)
AMINO ACID SENSING AND PROTEIN PRODUCTION
One important function of the combined efforts of lysosomes and mTOR is responding to a lack of amino acids in protein production. A particular amino acid, leucine, was found to produce a stimulant effect on mTOR. Recently, a similar response has been found for another amino acid called glutamine. What is striking is that these two mechanisms are completely independent, occurring in entirely separate cell compartments. Yet both interact with mTOR signals to regulate cellular growth.
It is not known if amino acid regulation is based on sensing just these two amino acids alone or whether other pathways haven’t been discovered yet. It is quite difficult to observe this type of signaling inside a cell. In any case, levels of these two amino acids are sensed by mTOR, and this triggers not just more recycling in lysosomes but also metabolic alterations to extract more amino acids from nutrients.
As well as regulating the use of amino acids in producing proteins, mTOR directs the genetic processes related to the protein manufacturing process in at least three distinct ways. Signals from mTOR influence proteins that increase or decrease production of particular messenger RNAs from DNA. They also influence enzymes that send messenger RNA to ribosomes. Also, at the ribosome, one end of the messenger RNA molecule needs to be stimulated by mTOR to start the process.
Research about regeneration after nerve injury has found more evidence about the ways mTOR stimulates the production of necessary proteins. When nerve damage occurs along the axon, signals first call for the production of mTOR molecules at the site of injury. Once multiple mTOR molecules are present, proteins needed for the repair are rapidly stimulated by these mTOR particles, using locally placed ribosomes and messenger RNAs.
ENERGY AND FOOD REGULATION
Somehow, mTOR monitors energy both at the cellular level and for the entire organism. Signaling with various organelles in the cell, mTOR picks up the amounts of energy-related nutrients available, such as lipids, then triggers their use to produce energy. At the same time, mTOR is at the center of the brain’s monitoring of energy for the entire organism.
Although regulation of eating to supply energy is not well understood, it appears to utilize multiple overlapping pathways. While there are many complex brain circuits involved, two opposing circuits are primary. mTOR signals are vital to both of these—increased appetite and obesity on the one hand and decreased eating and starvation on the other. One signal for having eaten enough causes mTOR to inhibit further intake. Another set of mTOR signals is involved in the effects of restricting calories to prevent aging.
OTHER mTOR EFFECTS ON THE BRAIN
Even more complex mTOR activity occurs in the brain. Circadian rhythms are a complex subject, since clocks have recently been found in all individual cells, in all organs, and in central brain regions. It is not yet clear how all these clocks interact with each other (described in chapter one). But it is known that various rhythms stimulate protein production through mTOR signals. It appears that mTOR signals are involved in brain synapses related to sleep, and that learning processes during sleep also have roots in mTOR signals.
Signals from mTOR complexes also affect the number of brain cells in the fetus and the creation of neural circuits. Abnormal mTOR levels in fetal growth produce brains with insufficient neurons, too many axons, distorted dendrite spines, and missing brain regions. In experiments, animals with altered mTOR show decreased learning ability and increased fearfulness. Misfolded proteins in brains can also trigger mTOR to inadvertently help cause degenerative brain disease.
mTOR signals are necessary for neuroplasticity, which rapidly builds and eliminates dendrites. Both mTOR complexes work together in this process. The first mTOR complex sends messenger RNAs and ribosomes by microtubule transport to the exact locations at a synapse to produce necessary proteins. Multiple proteins that hold the synapse together either strengthen or weaken the connection between the two neurons for the neuroplasticity effect. The second complex then stimulates the actin cytoskeleton to implement these alterations in axons and dendrites using the new proteins. Faulty signaling in any of these pathways leads to degenerative brain diseases.
An important aspect of brain development is directing migrating neurons and axons. mTOR signals are vital for setting up directional signals. Traveling axons search for distant destinations in the hugely complex brain architecture. Cues are provided by guidance molecules placed at particular locations along the way. Signals from mTOR stimulate local ribosomes to manufacture these proteins at the exact locations. In animal experiments, a lack of these mTOR signals and support molecules disrupts development of visual circuits.
mTOR’s WIDE-RANGING INFLUENCE
With its wide-ranging influences on cellular processes, mTOR is implicated in multiple diseases. Some of these are produced by reactive oxygen molecules that trigger mTOR to stop protein and energy production. Signals involving mTOR have been associated with an increase of abnormal misfolded proteins, such as amyloid and tau in Alzheimer’s disease and synuclein in Parkinson’s disease. Seizures have been treated by antagonizing mTOR with rapamycin. A new experimental treatment for depression with the anesthetic ketamine produces rapid results by stimulating mTOR pathways. However, rapamycin blocks the effect of this new treatment for depression.
It is surprising that one molecule can be involved in so many cellular processes. This raises questions about whether particular molecules have conversations in the same way that cells and organelles do. Previous chapters show conversations among all types of human cells and their organelles and even unicellular microbes that don’t have a nucleus. Even viruses, which defy the conventional definition of life, engage in complex communication processes. We are now learning more about communication that directly comes from such molecules as mTOR, which is somehow also at the center of multiple simultaneous signaling pathways.