Sleep all comes down to the mitochondria

science.org

593 points by A_D_E_P_T a day ago


A_D_E_P_T - a day ago

So the ancient mystery of why we need sleep might have just been answered.

The paper shows that cell‑autonomous mild uncoupling in Drosophila sleep‑inducing neurons -- via Ucp4A/Ucp4C -- keeps the flies awake by lowering mitochondrial Δp and therefore electron leak. This suggests a biochemical rationale for sleep -- which is postponed by the uncoupler. That form of pharmacological manipulation is also a very local intervention and likely has never been tried in mammals. (Most mitochondrial uncouplers aren't that specific and don't cross the BBB very well. Even "safe" new ones like BAM15.) If the paper is correct, not only is the mystery solved, but "healthy" wakefulness-promoting drugs might be on the horizon.

I'm curious about what this means for deep vs. light sleepers, and for people who need more or less sleep than others. Perhaps those traits are modifiable.

niemandhier - a day ago

"electrons flow through the respiratory chains of the respective feedback controllers like sand in the hourglass that determines when balance must be restored"

Wow, that is my new favorite sentence from any paper ever, replacing Mark Thomas' equally epic: "What it begins to suggest is that we’re looking at a Lord of the Rings-type world" from the legendary meeting at the Royal Society in London 2012/13.

https://www.nature.com/articles/nature.2013.14196

derbOac - a day ago

The paper is here:

https://www.nature.com/articles/s41586-025-09261-y

Not an expert in this area, but the essay feels a bit like an oversimplification. Not only is this in flies, but I wasn't entirely convinced this isn't about rest rather than sleep per se. It's a cool paper, interesting to read and read about, but my hunch is there's more steps in the chain, and am not sure it will replicate in humans or even mammals. But maybe I'll be wrong.

Symmetry - a day ago

Could this be an explanation for why people who go without sleep for long enough eventually just die? The Guinness Book of World Records doesn't accept records on staying awake for the same reason they don't accept records for the longest game of Russian Roulette.

amelius - a day ago

Something I thought was just an internet tale: mitochondria are close descendants of bacteria, and so taking antibiotics will potentially harm them. But turns out this is actually rooted in science ...

rajnathani - 4 hours ago

> .. the various modifications all point in the direction of a buildup of mitochondrial electron surplus as the fundamental inducer of the need to sleep.

> The hypothesis is that aerobic respiration itself comes with the tradeoff of a required sleep state in order to catch up and restore mitochondrial function in the nervous system ..

These are the key points. Then the explanation for insomnia for people who even engage in physical activity in non-successful attempts to mitigate it is that maybe the physical activity is overly exerting the body in a way which negatively affects the diaphragm muscles (including supporting muscles) and causes lower blood circulation and inhibits passive-physical-activity mitochondrial use in the body due to lower aerobic respiration mostly, and thus the electron surplus isn't then achieved for sleep-induction (as stated in the above quoted statement).

tgbugs - 15 hours ago

The relation of these results to natural short sleep [0] is of great interest. In particular the observation that individuals with these mutations also appear to be protected from Alzheimer's disease. A strong indication that these mutations may have some downstream interaction with the mitochondrial maintenance cycle described in the parent article.

0. https://en.wikipedia.org/wiki/Familial_natural_short_sleep

HarHarVeryFunny - 20 hours ago

There is a difference between being physically tired as a result of metabolic effort, and being mentally tired/sleepy. Even if you lie on the couch all day you will still be tired come night time, and can not survive for long if deprived of sleep.

It seems the mental need for sleep comes from the brain needing offline (no sensory input) downtime for "housekeeping" activities - perhaps essentially organizing and filing away the day's short-term memories.

BrenBarn - 5 hours ago

To what extent can this generalize from flies to humans? I've been very interested in dreams and read a decent amount of research on sleep and its functions, but most of that was years ago so my knowledge may be outdated. But my impression was that there are non-negligible differences in how sleep works (e.g., in terms of brain activity) between say, birds and mammals, or even one mammal to another. Certainly there could be some basal functions that are shared in flies but it seems a stretch to say "it all comes down to" that. As someone said in another comment, it's unclear what makes this about sleep rather than rest.

emsign - 20 hours ago

Increasing the count and efficiency of mitochondria is gonna be a big deal. ME/CFS is caused by these organelles not working as they should.

JCM9 - a day ago

Sleep is super important. I’ve seen too many workaholic types that barely sleep. So many of these folks end up with serious issues later in life.

pitched - 15 hours ago

ChatGPT is telling me that caffeine is an indirect UCP (uncoupled protein) activator, which I think is amazing. The one thing that we all use to keep ourselves awake can also make us need less sleep.

satvikpendem - a day ago

I wonder how this relates to sleep apnea, as in that state you sleep more the less oxygen you get. By the way, many people who don't think they have it yet feel tired during the day or simply feel like they need more sleep should get tested for it, as it's not just a problem for the obese.

bmillare - 16 hours ago

To me this paper confuses regulation via mitochondria from the requirement of sleep. Even if experimentally manipulating mitochondria state induces sleep, this might just be a proxy indicator control mechanism. ETC leak is only an issue for these dFBNs which are specifically complementary active to normal neuronal cells. I would say mitochondria are important for sleep regulation but this is specific to animals with brains. Other kingdoms do not "sleep". This is too much a stretch to say mitochondria dysfunction is the cause of sleep when other kingdoms also have mitochondrial stress and don't have actual analogical "sleep" processes. My raw take given my PhD work was on mitochondria.

skeezyboy - a day ago

i wonder if it relates to that chronic laziness disease, i cant remember what its called

phtrivier - a day ago

So, what products would work as "sleep in a pill", at least on the "not being exhausted" part (I suppose the "not getting crazy because of lack of REM sleep" would be different) ?

baggachipz - 20 hours ago

> If you need oxygen, then you need sleep!

Would this also correlate with the desire to yawn? I always heard that yawning was a response to needing more oxygen.

bluechair - 18 hours ago

I’m drawing a connection here between red light therapy being most beneficial if done in the morning.

Might mitochondria only be able to benefit from “recharging” in a recharge state?

Biochemists?

lr4444lr - a day ago

When he says lack of "restorative" sleep, he means stage III NREM? I wish he were more precise.

henryaj - a day ago

Given its role in energy transfer, does this suggest creatine might be a good supplement for improving sleep?

profsummergig - 13 hours ago

Mitochondria health all comes down to sleep.

dbagr - 21 hours ago

This has been known for a long time to those interested in the field.

andrethegiant - 17 hours ago

The mitochondria is the powerhouse of the cell

lawlessone - 18 hours ago

I wonder is this why creatine gives me more energy?

kwoff - 7 hours ago

"This also strongly suggests that sleep and hunger are both tied to mitochondrial function and energy balance (the latter was already pretty clear!), and that aerobic organisms are constantly adjusting for both fueling their mitochondria and giving them (especially the ones in the central nervous system) some down time for repair and recovery. As the authors say, rather eloquently, “electrons flow through the respiratory chains of the respective feedback controllers like sand in the hourglass that determines when balance must be restored”. There could well be many other functions that have since joined in with the sleep cycle (such as memory consolidation), but the authors hypothesize that mitochondrial function is the process that underlies all of them. If you need oxygen, then you need sleep!"

yawn :) I was wondering if sleep and hunger are tied to mitochondrial function, then wouldn't breathing be affected? If you're hungry, you're not getting enough glucose for respiration. If you're suffocating....

dist-epoch - 21 hours ago

The heart beats non-stop and doesn't sleep. How does this fit with this theory?

ashoeafoot - a day ago

So lack of sleep damages thr little critters.

NoMoreNicksLeft - 17 hours ago

I don't know if I can buy this explanation. Sleep is dangerous (and not just to night drivers). You're basically in a several-hours-long coma where a smilodon can come along and eat you without any trouble. So long as cells have more than one mitochondria each, staging them so they don't all need sleep simultaneously seems like a total no-brainer, and doesn't require any difficult-to-manage circumstances that leave you unconscious as predator snacks. This is a big deal, there's more than enough evolutionary pressure for sleep to have been selected out of the genome hundreds of millions of years ago.

m3kw9 - 17 hours ago

The body system is almost never one thing that drives it, especially sleep

dangoodmanUT - 18 hours ago

the powerhouse of the cell

searine - 19 hours ago

Funded primarily by UK and European taxpayers and foundations via 8 grants, predominantly from the Wellcome Trust, with additional support from EU research council and Swiss science programs.

bobafett-9902 - 17 hours ago

ah yes the mitochondria ... the powerhouse of the cell. thanks Ms Jeffers 7th grade bio

oc1 - a day ago

Crazy. If true this solves the question why humans need sleep and could be a great direction to resolve further question about sleep diseases.

ck2 - a day ago

mitochondria are just so incredibly fascinating in every aspect

they are like another lifeform not just living in our lifeform but making it possible

even their mere existence might be alien or even explain the lack of alien life detected so far

PBS Space Time has yet another awesome episode on that

https://www.pbs.org/video/is-there-a-simple-solution-to-the-...

https://www.youtube.com/watch?v=abvzkSJEhKk

beerws - a day ago

Happy to read that they didn't go for 'Mitochondria Are All You Need', such titles are making me tired

FrustratedMonky - a day ago

How far away are we from making this a pill? So we can stay up 18 hours a day, or something. Any estimates.

Any idea what foods or current methods, to trigger the same mechanism?

aussieguy1234 - a day ago

Electrons are all you need

boringg - 21 hours ago

Isn't mitochondria the hot new topic du jour (last couple of years) for bio? Is this kind of peak hype cycle?

Science follows the exact same cycle as tech ... I feel like the microbiome was huge and going to solve all our problems 8 years ago.

I don't want to sound jaded but history repeats itself in echoes - and these cycles seem somewhat predictable if the specific technology isn't predictable.