ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism.

ABSTRACT: Fatty acid β-oxidation is a central catabolic pathway with broad health implications. However, various fatty acids, including 4-hydroxy acids (4-HAs), are largely incompatible with β-oxidation machinery before being modified. Here we reveal that two atypical acyl-CoA dehydrogenases, ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains that phosphorylate the 4-hydroxy position as a requisite step in converting 4-hydroxyacyl-CoAs into conventional 2-enoyl-CoAs. Through cryo-electron microscopy and molecular modeling, we identified an atypical dehydrogenase binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas AC

SUBMITTER: Rashan EH 

PROVIDER: S-EPMC12440821 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature