In contrast to muscles and the like, nerves consume a surprising amount of energy even when they are at rest. A study now sheds light on why this is so. The permanently high fuel consumption has to do with a leak: With a considerable expenditure of energy, a constant loss of protons from the signal molecule stores in the synapses has to be compensated for. Such insights into the fundamentals of neural energy requirements are also of medical importance, the scientists emphasize.
The organ on which human success is based is an enormous energy guzzler: It only makes up around two percent of our body mass, but is responsible for around 20 percent of all energy consumption. It therefore needs around ten times more fuel in the form of glucose than other types of tissue. A large part of the consumption is due to the electrical activity. But the basal metabolic rate is also astonishingly high: examinations of patients in a coma show that energy consumption usually only drops by about half, even in electrically inactive states. The reasons for this energy consumption at rest are still largely unclear.
For a number of years now, Timothy Ryan’s scientists from Weill Cornell Medical College in New York have been studying the fundamentals of energy consumption in nerve tissues. The focus is on the synapses – the ends of the neuron extensions that connect them to other nerve cells. The researchers have already been able to show that the synapses consume large amounts of energy when they are active and are very sensitive to an interruption in their supply. The reason seems plausible: In the synapses, packing work has to be done constantly during activity – vesicles are loaded with neurotransmitters with energy expenditure. When the nerves work, these vesicles then open and release the signaling molecules into the synaptic gap. This creates a response in the connected partner neurons. If the nervous activity persists, new vesicles in the synapses have to be filled continuously.
Targeting dormant neurons
In their new study, however, the scientists examined the energy consumption in synapses when these are not actively participating in nerve communication. To do this, they investigated the energetic processes in cell cultures of neurons using a series of molecular biological and biochemical techniques. The nerve endings were in a state of rest or readiness. This means that the vesicles in the synapses were fully loaded with neurotransmitters – so energy-intensive packing work was no longer necessary.
The results of the investigation now showed: Despite the state of rest and the supposed inactivity, the fully loaded vesicles in the synapses showed considerable energy consumption. Further research results then shed light on the apparently paradoxical phenomenon: The researchers discovered that energy is constantly escaping from the vesicles: a “proton efflux” through their membranes emerged. They found indications that this energy loss is compensated for by a special “proton pump” enzyme: With considerable energy consumption, it brings the charge carriers that are important for the system back into the vesicles. In other words: fully loaded vesicles are leaking and the constant loss has to be compensated for by an energy-guzzling pump system.
Expensive compensation
But how does the problematic loss come about? The team’s experiments have already provided initial indications of this as well: Certain transporter proteins are apparently responsible for the proton leaks. As the scientists explain, these units smuggle the neurotransmitters into the vesicles when they are loaded. To do this, they have to change their shape, releasing a proton. The researchers now suspect that the shape-changing processes of these transporters continue even after the vesicles have been loaded, which is associated with a release of protons.
According to them, it is possible that the threshold for the change in shape of the transporter is set low in order to enable faster reloading of neurotransmitters during synaptic activity and thus faster thinking and acting. “The disadvantage of a faster charging capacity would be that even random heat fluctuations could trigger the change in shape of the transporter, which would lead to a constant loss of energy, even if no neurotransmitter is being charged,” explains Ryan. Although the effect appears to be small with a single vesicle, the bottom line is that it is of great importance – this is especially true in the comparatively huge human brain: “With the billions of synaptic vesicles, it adds up,” says Ryan.
The results are thus a step forward in understanding the basic biology of the brain: “They help us, for example, to better understand why the human brain is so sensitive to the interruption or weakening of its fuel supply,” says Ryan. This, in turn, has a medical relevance: Undersupply is a major problem in neurology, and metabolic deficits have been identified in a number of common brain diseases such as Alzheimer’s and Parkinson’s. Basic neurological research, as in the current case, could ultimately help solve important medical riddles and develop new treatment methods.
Source: Weill Cornell Medicine, Article: Science Advances, doi: 10.1126 / sciadv.abi9027