Sleep, ageing and the fires of life

April 11, 2019

Sleep deprivation elevates mitochondrial reactive oxygen species in sleep-promoting neurons, which register this rise with the help of a redox-sensitive ion channel. The resulting changes in electrical excitability close a molecular feedback loop that leads to the induction of sleep.

It is no accident that oxygen tanks carry explosion hazard labels: uncontrolled combustion is dangerous.

Humans and animals face similar risks when they use the oxygen they breathe to convert food into energy. To contain these risks, food is combusted in specialised structures called mitochondria, which are present in virtually every cell. Mitochondrial combustion is tightly controlled but not failsafe. When a cell’s mitochondria are supplied with more fuel than the cell can use, the cell suffers ‘oxidative stress’.

Oxidative stress is believed to be a reason for why we age and a culprit for the degenerative diseases that blight our later years. Diets that restrict caloric intake may be beneficial because they limit the amount of fuel mitochondria can burn.

Writing in the journal Nature, the Miesenböck group now report that oxidative stress is also a root cause of sleep. The team studied the regulation of sleep in fruit flies. Each fly has around two dozen sleep-control neurons, brain cells that are also found in other animals and thought to exist in people. In previous research, Miesenböck’s team discovered that these sleep-control neurons act as an on–off switch: If the neurons are electrically active, the fly is asleep; when they are silent, the fly is awake.

Seoho Song, one of the two lead authors of the new study, says: ‘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,’ says Song: ‘What causes the electrical current to flow through Shaker?’

The team found the answer in a component of the Shaker channel itself.

Lead author Anissa Kempf explains: ‘Suspended underneath the electrically conducting portion of Shaker is its β-subunit, like the gondola under a hot air ballon. 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, which drives the conversion.’

In a striking demonstration of this mechanism, a flash of light that flipped the chemical state of NADPH put flies to sleep.

Drugs that change the chemistry of Shaker-bound NADPH in an analogous manner could be a powerful new type of sleeping pill. ‘Sleep disturbances are very common,’ says Miesenböck, ‘and sleeping pills are among the most commonly prescribed medicines. But existing drugs carry risks of confusion, forgetfulness and addiction. Targeting the mechanism we have discovered could possibly avoid some of these side effects.’

A potassium channel β-subunit couples mitochondrial electron transport to sleep by Anissa Kempf, Seoho M. Song, Clifford B. Talbot and Gero Miesenböck. Nature (2019)


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