Ether glycerophospholipid control of peroxisome degradation confers protection from ischemia
- 1Department of Medicine, Massachusetts General Hospital, Harvard Medical School
Abstract
Ether glycerophospholipids (ether lipids) are a subclass of glycerophospholipids that are synthesized at the peroxisome and constitute nearly 20% of the total phospholipid content in metazoans. Biochemically, ether lipids have an alkyl chain attached by an ether bond at the sn-1 position of the glycerol backbone (alkyl-ether) primarily containing choline or ethanolamine head groups. Some ether lipids contain a cis bond adjacent to the ether linkage (alkenyl-ether) and are commonly referred to as plasmalogens. While the importance of ether lipids in humans is clear, highlighted by the severity of inherited peroxisomal disorders caused by ether lipid deficiency, the molecular roles of these lipids remain poorly understood. Here, we identify a link between ether lipid metabolism, peroxisome degradation, and oxygen availability. We find Fatty acyl-CoA-reductase 1 (FAR1), the rate-limiting enzyme in peroxisomal ether lipid metabolism, acts as a peroxisome receptor necessary for peroxisome degradation when oxygen is limiting. Hypoxia increases choline ether lipid abundance, promotes autophagy activation, and peroxisome degradation. Mechanistically, FAR1 binds ATG8-family protein LC3B and is necessary and sufficient to control peroxisome degradation under hypoxia. FAR1s enzymatic function as well as its capacity to bind LC3B is necessary to degrade peroxisomes under hypoxia. Similarly, loss of multiple components of peroxisomal ether lipid metabolism blocks peroxisome degradation under hypoxia in cells and in vivo. In mouse models of chronic HIF activation, Far1 is a direct HIF target gene and is necessary for peroxisome degradation in this setting. Increasing ether lipids using ether lipid precursors activates autophagy and promotes autophagy-dependent cardioprotection against ischemic injury. This work reveals FAR1 as a critical regulator of peroxisome homeostasis in the setting of oxygen limitation.
Related
- Peroxisome quality control is gated by a dynamic ATF6α-ABCD3 tether
- Protection of beta-blocker and 5-hydroxytryptamine 1A receptor agonist on myocardial ischemia injury in rats by regulating the NLRP3/Caspase-1/GSDMD pathway
- Phosphatidic acid acts as a signaling lipid to direct glycerolipid versus glycerophospholipid flux in chicken muscle
- Sandwich-structured PVDF/protein piezoelectric hydrogel regulates osteogenesis and adipogenesis through glycerophospholipid metabolism in osteoporotic inflammatory bone defects
- Impaired Peroxisome Import Drives Cellular Senescence through SCAF1-Dependent Suppression of Mitoribosome Biogenesis
BibTeX
@misc{singh2026ether,
title = {{Ether glycerophospholipid control of peroxisome degradation confers protection from ischemia}},
author = {M. Singh and S. Qayyum and G. Godoy and J. Benhalima and O. Seidel and N. Madl and K. Watschinger and A. A. Deik and H. Keshishian and C. B. Clish and S. A. Carr and G. Wyant},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.755133},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.755133v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Ether glycerophospholipid control of peroxisome degradation confers protection from ischemia
AU - M. Singh
AU - S. Qayyum
AU - G. Godoy
AU - J. Benhalima
AU - O. Seidel
AU - N. Madl
AU - K. Watschinger
AU - A. A. Deik
AU - H. Keshishian
AU - C. B. Clish
AU - S. A. Carr
AU - G. Wyant
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.755133
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.755133v1
AB - Ether glycerophospholipids (ether lipids) are a subclass of glycerophospholipids that are synthesized at the peroxisome and constitute nearly 20% of the total phospholipid content in metazoans. Biochemically, ether lipids have an alkyl chain attached by an ether bond at the sn-1 position of the glycerol backbone (alkyl-ether) primarily containing choline or ethanolamine head groups. Some ether lipids contain a cis bond adjacent to the ether linkage (alkenyl-ether) and are commonly referred to as plasmalogens. While the importance of ether lipids in humans is clear, highlighted by the severity of inherited peroxisomal disorders caused by ether lipid deficiency, the molecular roles of these lipids remain poorly understood. Here, we identify a link between ether lipid metabolism, peroxisome degradation, and oxygen availability. We find Fatty acyl-CoA-reductase 1 (FAR1), the rate-limiting enzyme in peroxisomal ether lipid metabolism, acts as a peroxisome receptor necessary for peroxisome degradation when oxygen is limiting. Hypoxia increases choline ether lipid abundance, promotes autophagy activation, and peroxisome degradation. Mechanistically, FAR1 binds ATG8-family protein LC3B and is necessary and sufficient to control peroxisome degradation under hypoxia. FAR1s enzymatic function as well as its capacity to bind LC3B is necessary to degrade peroxisomes under hypoxia. Similarly, loss of multiple components of peroxisomal ether lipid metabolism blocks peroxisome degradation under hypoxia in cells and in vivo. In mouse models of chronic HIF activation, Far1 is a direct HIF target gene and is necessary for peroxisome degradation in this setting. Increasing ether lipids using ether lipid precursors activates autophagy and promotes autophagy-dependent cardioprotection against ischemic injury. This work reveals FAR1 as a critical regulator of peroxisome homeostasis in the setting of oxygen limitation.
ER -