Roles of endogenous ether lipids and associated PUFAs in the regulation of ion channels and their relevance for disease

Abstract

Ether lipids (ELs) are lipids characterized by the presence of either an ether linkage (alkyl lipids) or a vinyl ether linkage [i.e., plasmalogens (Pls)] at the sn1 position of the glycerol backbone, and they are enriched in PUFAs at the sn2 position. In this review, we highlight that ELs have various biological functions, act as a reservoir for second messengers (such as PUFAs) and have roles in many diseases. Some of the biological effects of ELs may be associated with their ability to regulate ion channels that control excitation-contraction/secretion/mobility coupling and therefore cell physiology. These channels are embedded in lipid membranes, and lipids can regulate their activities directly or indirectly as second messengers or by incorporating into membranes. Interestingly, ELs and EL-derived PUFAs have been reported to play a key role in several pathologies, including neurological disorders, cardiovascular diseases, and cancers. Investigations leading to a better understanding of their mechanisms of action in pathologies have opened a new field in cancer research. In summary, newly identified lipid regulators of ion channels, such as ELs and PUFAs, may represent valuable targets to improve disease diagnosis and advance the development of new therapeutic strategies for managing a range of diseases and conditions.

Plasmalogen-Based Liquid Crystalline Multiphase Structures Involving Docosapentaenoyl Derivatives Inspired by Biological Cubic Membranes

“…It should be noted that a bilayer thickness mismatch in mixed lipid membranes controls the domain size and the phase separation, which is of crucial importance for the embedded proteins. Thickening of the lipid bilayers may dramatically influence the organization of membrane proteins ( Dean and Lodhi, 2018 ; Fontaine et al, 2020 ). It is known that membrane receptor clustering and domain formation may interfere with the protein function and signaling activation ( Angelov and Angelova, 2017 ).…”

“…Decreased ethanolamine plasmalogen levels have been established with the progression of Alzheimer’s (AD) and Parkinson’s (PD) diseases, psychiatric disorders, and also in neuromuscular impairments, glaucoma, coronary artery disease, and acute myocardial infarction ( Farooqui et al, 1997 ; Dragonas et al, 2009 ; Brodde et al, 2012 ; Sutter et al, 2016 ; Dorninger et al, 2017a , b , 2019 ; Paul et al, 2019 ; Su et al, 2019 ). The plasmalogen lipids modulate the membrane fluidity and dynamics, influence the membrane protein organization, and provide reservoirs of secondary messengers as well as precursors of inflammatory mediators ( Bogdanov et al, 1999 ; Thai et al, 2001 ; Mannock et al, 2010 ; Koivuniemi, 2017 ; Jenkins et al, 2018 ; Pohl and Jovanovic, 2019 ; Fontaine et al, 2020 ). The vinyl ether moiety at the sn-1 position of glycerol backbone is significant for the antioxidant (scavenger) properties of plasmalogens and the protection of neuronal, cardiac, and muscle cells from oxidative stress ( Reiss et al, 1997 ; Zoeller et al, 1999 ; Leßig and Fuchs, 2009 ; Wallner and Schmitz, 2011 ; Yamashita et al, 2015 ; Sibomana et al, 2019 ).…”

Alterations in complex lipids in tumor tissue of patients with colorectal cancer

“…However, their exact role in promoting cancer progression is not known. It has been shown that they regulate ion channels, which may constitute the mechanism underlying the regulation of cell proliferation [52]. Likewise, the exact nature of sphingolipid metabolism in carcinogenic processes is not yet clear, but seems to be dependent on acyl-chain composition [53].…”

Plasmalogens, platelet-activating factor and beyond – Ether lipids in signaling and neurodegeneration

“…Despite the contrasting reports, the case for a plasmalogen deficit in AD is strong and further emphasized by studies showing that not only PlsEtn, but also PlsCho is affected ( Grimm et al, 2011a ; Igarashi et al, 2011 ) and by the analyses of brain lipids in various mouse models of AD ( Han et al, 2001 ; Fabelo et al, 2012 ; Tajima et al, 2013 ; Uruno et al, 2020 ). A detailed overview of the extent of plasmalogen alterations at the species level in published studies involving human AD patients was presented in a recent review ( Fontaine et al, 2020 ).…”