Mitochondrial autophagy in the sleeping brain

Abstract

A significant percentage of the mitochondrial mass is replaced on a daily basis via mechanisms of mitochondrial quality control. Through mitophagy (a selective type of autophagy that promotes mitochondrial proteostasis) cells keep a healthy pool of mitochondria, and prevent oxidative stress and inflammation. Furthermore, mitophagy helps adapting to the metabolic demand of the cells, which changes on a daily basis.Core components of the mitophagy process are PINK1 and Parkin, which mutations are linked to Parkinson’s Disease. The crucial role of PINK1/Parkin pathway during stress-induced mitophagy has been extensively studied in vitro in different cell types. However, recent advances in the field allowed discovering that mitophagy seems to be only slightly affected in PINK1 KO mice and flies, putting into question the physiological relevance of this pathway in vivo in the whole organism. Indeed, several cell-specific PINK1/Parkin-independent mitophagy pathways have been recently discovered, which appear to be activated under physiological conditions such as those that promote mitochondrial proteome remodeling during differentiation or in response to specific physiological stimuli.In this Mini Review we want to summarize the recent advances in the field, and add another level of complexity by focusing attention on a potentially important aspect of mitophagy regulation: the implication of the circadian clock. Recent works showed that the circadian clock controls many aspects of mitochondrial physiology, including mitochondrial morphology and dynamic, respiratory activity, and ATP synthesis. Furthermore, one of the essential functions of sleep, which is controlled by the clock, is the clearance of toxic metabolic compounds from the brain, including ROS, via mechanisms of proteostasis. Very little is known about a potential role of the clock in the quality control mechanisms that maintain the mitochondrial repertoire healthy during sleep/wake cycles. More importantly, it remains completely unexplored whether (dys)function of mitochondrial proteostasis feedbacks to the circadian clockwork.

Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR

“…Melatonin may induce mitophagy-associated regulators except NIX. In fact, several studies have revealed that melatonin enhances mitophagy by the PINK1-parkin pathway or autophagy-related genes in brain ischemia, acute brain injury, or Parkinson’s disease models all of which are quite different from glucocorticoid-induced neurodegeneration [ 52 , 54 ]. We did not screen for these pathways in other brain regions including substantia nigra or cortex, meaning that melatonin can alleviate glucocorticoid-induced impaired mitophagy by increasing PINK1-parkin pathways in these regions.…”

Insomnia in Forensic Detainees: Is Salience Network the Common Pathway for Sleep, Neuropsychiatric, and Neurodegenerative Disorders?

“…Mitochondrial trafficking as well as autophagy (mitophagy) occur during sleep, probably explaining the reason most living beings require rest [ 154 ]. Interestingly, serotonin (5-HT) promotes mitochondrial transport in hippocampal neurons, suggesting that antidepressant drugs, serotonin reuptake inhibitors (SSRIs), may “exert their action by supplying healthy mitochondria to stressed neurons [ 155 ].…”

The Dynamic Relationship between the Glymphatic System, Aging, Memory, and Sleep

“…The clearance of these molecules is obviously vital, particularly in the case of the amyloid beta (Aβ) peptide, a byproduct mostly of membrane maintenance, which negatively affects neurons by coalescing into amyloid plaques, a key factor in the pathogenesis of AD and neurodegeneration in general [ 37 , 38 ]. The interplay between synaptic activity, mitochondrial function, and sleep is crucial in maintaining a healthy brain [ 39 ]. Sleep abnormalities can disrupt the typical energy metabolism of cells, including those located within the brain.…”