Oxford University researchers have discovered a brain process common to sleep and aging in research that could pave the way for new treatments for insomnia.
Writing in the journal Nature, the scientists report how oxidative stress leads to sleep.
Oxidative stress is also believed to be a reason why we age and a cause of degenerative diseases.
Oxygen is often referred to as the Janus gas, as it has both positive benefits and potentially damaging side-effects for biological systems.
Reactivity allows oxygen to participate in high-energy electron transfers, and hence support the generation of large amounts of adenosine-5-triphosphate (ATP) through oxidative phosphorylation.
This is necessary to permit the evolution of complex multicellular organisms, but also renders it liable to attack any biological molecule, be it a protein, lipid or DNA.
Consequently, our body is under constant oxidative attack from reactive oxygen species (ROS).
A complex system of antioxidant defences has evolved that generally holds this attack in balance.
On occasions, however, this balance can be perturbed, leading to oxidative stress.
Because of the multiple and diverse effects that oxygen toxicity can have on a cell, oxidative stress is best defined in broad terms as an alteration in the pro-oxidant–antioxidant balance in favour of the former that leads to potential damage.1
Oxidative stress is now recognised to play a central role in the pathophysiology of many different disorders, including complications of pregnancy.
The concept of a pro-oxidant–antioxidant balance is central to an understanding of oxidative stress for several reasons.
Firstly, it emphasises that the disturbance may be caused through changes on either side of the equilibrium (e.g. abnormally high generation of ROS or deficiencies in the antioxidant defences).
Secondly, it highlights the homeostatic concentrations of ROS. Although ROS first came to the attention of biologists as potentially harmful by-products of aerobic metabolism, it is now recognised that they play important roles as secondary messengers in many intracellular signalling pathways.2
Finally, the concept of a balance draws attention to the fact that there will be a graded response to oxidative stress.
Hence, minor disturbances in the balance are likely to lead to homeostatic adaptations in response to changes in the immediate environment, whereas more major perturbations may lead to irreparable damage and cell death.
The boundary between normal physiological changes and pathological insults is therefore inevitably indistinct.
The definition of oxidative stress provided above is necessarily broad because the outcome depends in part on the cellular compartment in which the ROS are generated.
There are many potential sources of ROS, and the relative contributions of these will depend on the environmental circumstances prevailing.
As the reactions of ROS are often diffusion-limited, the effects on cell function depend to a large extent on the biomolecules in the immediate vicinity. Different insults will therefore generate different outcomes.
A further feature of oxidative stress that affects its clinical presentation is that it rarely occurs in isolation.
It is now appreciated that complex interactions take place between oxidative and other forms of cell stress, such as endoplasmic reticulum (ER) stress.
The clinical manifestation will therefore depend on the balance of metabolic activities in a particular cell type or organ, and so may vary from system to system.
The researchers say the discovery brings us closer to understanding the still-mysterious function of sleep and offers new hope for the treatment of sleep disorders.
It may also explain why, as is suspected, chronic lack of sleep shortens life.
Professor Gero Miesenböck, Director of Oxford University’s Centre for Neural Circuits and Behaviour, who led the Oxford team, said:
‘It’s no accident that oxygen tanks carry explosion hazard labels: uncontrolled combustion is dangerous.
Animals, including humans, face a similar risk when they use the oxygen they breathe to convert food into energy: imperfectly contained combustion leads to “oxidative stress” in the cell.
This is believed to be a cause of aging and a culprit for the degenerative diseases that blight our later years.
Our new research shows that oxidative stress also activates the neurons that control whether we go to sleep.’
The team studied the regulation of sleep in fruit flies – the animal that also provided the first insight into the circadian clock nearly 50 years ago.
Each fly has a special set of sleep-control neurons, brain cells that are also found in other animals and believed to exist in people.
In previous research, Professor Miesenböck’s team discovered that these sleep-control neurons act like an on-off switch: if the neurons are electrically active, the fly is asleep; when they are silent, the fly is awake.
Dr. Seoho Song, a former graduate student in the Miesenböck lab and one of the two lead authors of the study, said:
‘We decided to look for the signals that switch the sleep-control neurons on. We knew from our earlier work that a main difference between sleep and waking is how much electrical current flows through two ion channels, called Shaker and Sandman. During sleep, most of the current goes through Shaker.’
Ion channels generate and control the electrical impulses through which brain cells communicate.
‘This turned the big, intractable question “Why do we sleep?” into a concrete, solvable problem,’ said Dr. Song.
‘What causes the electrical current to flow through Shaker?’
The team found the answer in a component of the Shaker channel itself.
The researchers say the discovery brings us closer to understanding the still-mysterious function of sleep and offers new hope for the treatment of sleep disorders.
It may also explain why, as is suspected, chronic lack of sleep shortens life.
Lead author and postdoctoral fellow in the Miesenböck group, Dr Anissa Kempf, explained: ‘Suspended underneath the electrically conducting portion of Shaker is another part, like the gondola under a hot air balloon.
A passenger in the gondola, the small molecule NADPH, flips back and forth between two chemical states – this regulates the Shaker current.
The state of NADPH, in turn, reflects the degree of oxidative stress the cell has experienced. Sleeplessness causes oxidative stress, and this drives the chemical conversion.’
In a striking demonstration of this mechanism, a flash of light that flipped the chemical state of NADPH put flies to sleep.
According to Professor Miesenböck, drugs that change the chemistry of Shaker-bound NADPH in the same way could be a powerful new type of sleeping pill.
‘Sleep disturbances are very common,’ he said, ‘and sleeping pills are among the most commonly prescribed drugs. But existing medications carry risks of confusion, forgetfulness and addiction. Targeting the mechanism we have discovered could avoid some of these side effects.’
Source:
University of Oxford
Media Contacts:
Stuart Gillespie – University of Oxford
Image Source:
The image is in the public domain.
Original Research: Closed access
“A potassium channel β-subunit couples mitochondrial electron transport to sleep”
Anissa Kempf, Seoho M. Song, Clifford B. Talbot & Gero Miesenböck
Nature (2019) doi:10.1038/s41586-019-1034-5
