ACAD10 encodes two long-sought orphan enzymes in ether lipid metabolism: the kinase domain functions as 1-O-alkylglycerol kinase in the dietary salvage pathway, while the phosphatase domain functions as 1-O-alkyl-2-acetyl-sn-glycero-3-phosphate phosphatase in platelet-activating factor biosynthesis, with loss of ACAD10 function impairing ether lipid salvage in C. elegans and mice and disease-associated ACAD10 polymorphisms correlating with reduced plasma ether lipid levels in humans.

Ether lipids play critical roles in membrane dynamics, antioxidant defense, and signaling. They comprise ∼20% of mammalian phospholipids, and disruptions in their metabolism cause severe genetic disorders and are associated with neurodegenerative and metabolic diseases. Ether lipids are synthesized de novo from glycolytic intermediates or salvaged from the diet. While the products of these pathways are known, several key enzymes remain unidentified, including the 1-O-alkylglycerol kinase and the 1-O-alkyl-2-acetyl-sn-glycero-3-phosphate phosphatase. Here, we show that acyl-CoA dehydrogenase member 10 (ACAD10) catalyzes the phosphorylation of 1-O-alkylglycerols and the dephosphorylation of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphate. Worms and mice lacking ACAD10 have reduced ether lipid levels and cannot salvage dietary alkylglycerols. Furthermore, individuals from the Akimel O’odham (Pima) tribe carrying ACAD10 polymorphisms also show decreased plasma ether lipid levels. Collectively, our findings resolve two long-standing gaps in ether lipid biochemistry and reveal a mechanistic link between ether lipid metabolism and a population-associated risk factor for type 2 diabetes.