IT IS HARD to overstate the importance of sleep. Regular hours of rest offer organisms of all sizes a chance to consolidate memories, repair cells and boost the health of their immune systems. But the source of the urge to sleep, known to scientists as sleep pressure (and everyone else as tiredness), has remained elusive.
Many theories have been put forward. One pins the blame on the build-up of a brain chemical called adenosine. Another points the finger at the brain’s need to build synaptic connections.
A study published in Nature on July 16th offers the strongest evidence yet that the urge to sleep is caused by a build-up of electrons in the mitochondria of certain brain cells. If true, sleep may have originally emerged as a way of repairing mitochondria, with its other benefits evolving later.
Mitochondria, which can be found in almost all human and animal cells, supply energy by stripping electrons from fuel molecules derived from food. But some electrons leak out of the mitochondria while this takes place, reacting with oxygen to produce toxic by-products that can damage the mitochondria, as well as other parts of the cell, if they build up.
The new study suggests that when too much mitochondrial damage is detected in brain cells known as sleep-control neurons, they trigger sleep. These neurons act like circuit-breakers, says Gero Miesenböck at Oxford University, one of the paper’s lead authors, tripping the brain into sleep before too many electrons build up. Sleep simultaneously restores the balance of electrons and allows the mitochondrial damage to be repaired.
To reach their conclusions, the scientists conducted a series of experiments on fruit flies. They started by labelling the sleep-control neurons in the flies’ brains, known as dorsal fan-shaped body neurons (dFBNs), with a genetically engineered protein that made them glow green. They then disrupted the flies’ natural sleep cycles by placing them on a platform that was kept in constant motion for 12 hours.
When the fluorescent dFBNs were subsequently viewed under a microscope, the mitochondria within were found to have split apart, a sign of electron-related damage. After a period of sleep, however, they had fused back together.
This suggested that mitochondrial damage might drive the urge to sleep. To determine if the relationship was causal, the scientists then manipulated the balance of electrons in the mitochondria in several other ways.
Most telling was an experiment in which the researchers provided mitochondria in the dFBNs with an alternative power source: namely a protein that uses light for energy. When the researchers shone a flashlight on flies that were not sleep-deprived, their mitochondria could supply energy without needing to use their stash of electrons. This increased the chance of an electron leak. Within the first hour of exposure to the flashlight the engineered flies were much more likely to fall asleep than those in control groups.
Ivana Rosenzweig, a specialist in the neuroscience of sleep at King’s College London who was not involved in the study, says that the findings represent a significant conceptual shift.
Although electron imbalance in mitochondria had been suspected to correlate with a lack of sleep, she believes this study provides evidence that it may be the cause of sleep pressure.
As the way cells are supplied with energy is closely linked to sleep across many animal species, the authors say it is likely that electron build-up could cause sleep pressure in humans, too.
They further note that humans with mitochondrial disorders often report a feeling of sleepiness unrelated to muscle fatigue. Professor Miesenböck hopes that a better understanding of sleep pressure will help shed light on a range of sleep disorders and chronic conditions that count fatigue as a symptom. ■
