The origins of sleep may be metabolic – to reduce reactive oxygen species (ROS), driven by fat oxidation
-
A fascinating study that again highlights the central role metabolism plays in activities medicine considers weakly linked or unrelated to metabolism. Namely, the study suggests that the primary trigger of sleep is the accumulation of ROS, which under normal conditions form mostly as a result of excessive fat oxidation, which itself happens mostly under stress. Virtually all ROS is formed as a result of so-called reverse electron flow (REF), which excessive fat oxidation triggers by forming a functional block at electron transport chain (ETC) complex II. ETC II is crucially dependent on the cofactor FAD (synthesized from vitamin B2), and excessive fat oxidation consumes a lot of FAD through the beta-oxidation pathway that precedes entry of fatty acid metabolites into the Krebs cycle. Since high levels of ROS are toxic to cells, it makes perfect sense for organisms to develop an evolutionary conserved (across species and time) mechanism such as sleep that forces the organism to drastically reduced physical/mental activity, which in turn reduces excessive fat oxidation and thus ROS production. The findings of the study are anecdotally corroborated by multiple reports from people who practice long-distance endurance exercise (which yours truly also used to (ab)use years ago and thus caused severe health disturbances). Namely, they all feel extremely sleepy after a bout of such exercise and often usually sleep for much longer periods of time at night compared to days without such exercise (or less acute stress). Babies are also good example, as they invariably get very sleepy after a stressful or exhausting event, especially if not well-fed prior to the event, thus increasing fatty acid oxidation further. Finally, chemicals that increase electron leakage into the mitochondrial matrix such as 2,4-dinitrophenol (DNP), are also known to cause sleepiness. There is also the co-called “central fatigue” hypothesis, which postulates that fatigue and sleepiness are caused by elevation of brain serotonin and such elevations are known to happen when blood levels of fatty acids are elevated, which results in displacement of tryptophan from albumin and thus increased entry into the brain, leading to increased serotonin synthesis. Interventions that lower fat oxidation and/or brain serotonin are known to largely prevent the feelings of fatigue and sleepiness, thus corroborating the study findings. Aspirin, which lowers both blood levels of fatty acids as well as plasma serotonin has a known anti-fatigue effect, confirmed in multiple human studies with patients suffering from conditions characterized by debilitating fatigue and daytime sleepiness (e.g. multiple sclerosis, Crohn’s disease, ulcerative colitis, diabetes, cancer, etc).
https://www.nature.com/articles/s41586-025-09261-y
https://www.the-scientist.com/animals-sleep-because-electrons-leak-73356
“…Recently, researchers discovered that buildup of toxic molecules in the mitochondria could be the answer they’ve been looking for.1 Gero Miesenböck, a neuroscientist at the University of Oxford, and his colleagues showed that the extent of electron leakage from the electron transport chain in the mitochondria determined how much fruit flies slept. Their findings, published in Nature, suggest a mechanistic reason for why different animals, including humans, need sleep.”
“…To generate energy, cells transport electrons from the Krebs cycle across four protein complexes within the inner mitochondrial membrane in a process known as cellular respiration. This electron flow establishes a proton gradient across the mitochondrial membrane, which ATP synthase can harness to make ATP. Once electrons finally reach cytochrome c oxidase (Complex IV), they combine with hydrogen protons and oxygen to form water. But sometimes, electrons can leak into the mitochondrial matrix before getting to the end of the transport chain. When this happens, electrons can reduce free oxygen to form reactive oxygen species, which are toxic to cells. Metabolically active cells, such as neurons, are especially prone to such leakage. “The respiratory chain handles single, unpaired electrons, and if you do that in the presence of oxygen, you’re almost asking for an electron leak,” Miesenböck said. “Life wants to use respiration because the energy gains are so large, but it has to somehow deal with the electron leak, and one way to deal with it is sleep. We think that’s the big trade-off that’s at the heart of all of it.”
“…Next, to understand how cellular respiration regulates sleep, Miesenböck and his colleagues manipulated electron transport in opposite directions. First, the researchers overexpressed proteins that could dissipate the ATP-generating proton gradient in fly dFBNs. By increasing the demand for metabolically generated electrons, this reduced electron leakage. As a result, the flies slept less. Conversely, the researchers mimicked the increase in mitochondrial electron leakage by outsourcing ATP synthesis via the expression of an archaeal proton pump. This manipulation made electrons from the Krebs cycle redundant, and it increased the time that flies spent asleep. “One obvious question to ask is whether the same thing is also happening in the mammalian brain,” Miesenböck said. “I would think so, but formally, it needs to be proven.” Savage said, “This study gives strong evidence that the primary driving force of sleep is to counteract [fat] metabolism, but it doesn’t mean that some other functions, like memory consolidation or immune system boosting, haven’t piggybacked on top.”
-
@haidut
Thanks a lot for this and all the other posts, we missed you so much! I read the paper and even though the authors claim that the purpose of sleep is to dissipate electrons, I struggle to get if they have really proven that. With their manipulations, I think they clearly showed what Dr Peat always said that sleep is an energy demanding process. What do you think? Nevertheless I agree that it is probably a way to antagonise electron leakage from fat metabolism.