Journal of Molecular BiologyVolume 437, Issue 18, 15 September 2025, 169227Author links open overlay panel, , , Highlights•

Autophagy and sleep play contrasted and complementary roles in maintaining homeostasis.

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Sleep impairment increases autophagy, but whether this is beneficial or detrimental is still debated.

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Levels of autophagosome may modulate sleep amount.

Abstract

Autophagy and sleep are two evolutionary conserved mechanisms across the animal kingdom. Autophagy is a pathway for the degradation of cytoplasmic material in the lysosome, playing important roles in the homeostasis and health of the organism. On the other hand, sleep is a homeostatically regulated state with numerous presumed essential roles, including the restoration of tissue and physiological functions, such as brain waste clearance via the activation of the glymphatic systems. Given that sleep and autophagy are crucial processes tightly linked to homeostasis and maintenance of good health, understanding how they interact is of great interest, especially as sleep quality decreases in our modern 24-hour societies. Autophagy represents a promising target for therapeutic interventions in this context. Here, we review the contrasted and complementary roles of autophagy and sleep in maintaining homeostasis. Specifically, we focus on recent evidence suggesting that sleep impairment may increase autophagy, while autophagosome levels may modulate the amount of sleep. We discuss outstanding questions at the intersection of these two fields, highlighting methodological shortcomings in the current literature. Overcoming these limitations will be instrumental to design new experiments with the aim of answering one of the greatest mysteries of our time – why do we sleep?

Graphical abstractDownload: Download high-res image (131KB)Download: Download full-size imageAbbreviationsATP

Adenosine triphosphate

AMPK

Adenosine monophosphate activated protein kinase

BMAL1

Basic helix-loop-helix ARNT-like protein 1

CLOCK

Circadian locomotor output cycles kaput

CMA

Chaperone-mediated autophagy

CRH

corticotropin-releasing hormone

CRFR

Corticotropin-releasing hormone receptor

CRISPR

clustered regularly interspaced short palindromic repeats

GABA

Gamma-aminobutyric acid

GABARAP

GABA type A receptor associated protein

GFP

Green fluorescent protein

HPA

hypothalamic–pituitary–adrenal

ipRGCs

intrinsically photoreceptive retinal ganglion cells

LAMP1

Lysosomal-associated membrane protein 1

LC3

Microtubule-associated protein 1A/1B-light chain 3

lLNv

large ventrolateral neurons

MMPM

Modified multiple platform method

mTORC1

mammalian target of rapamycin complex 1

NAD

Nicotinamide adenine dinucleotide

NREM

Non rapid eye movement

PDF

pigment dispersing factor

ROS

reactive oxygen species

SCN

Suprachiasmatic nucleus

sLNv

small ventrolateral neurons

qPCR

Quantitative polymerase chain reaction

TEM

Transmission electron microscopy

TFEB

transcription factor EB

TMS

transcranial magnetic stimulation

Keywords

autophagy

sleep

homeostasis

circadian rhythm

macroautophagy

© 2025 The Author(s). Published by Elsevier Ltd.