Paper
Document
Download
Flag content
0

ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism

Authors
Edrees H. Rashan,Abigail K. Bartlett
Daven B. Khana,Jingying Zhang,Raghav Jain,Andrew J. Smith,Zakery N. Baker,Taylor Cook,Alana Caldwell,Autumn R. Chevalier,Brian F. Pfleger,Peng Yuan,Daniel Amador-Noguez,Judith A. Simcox,David J. Pagliarini,Edrees Rashan,Adrienne Bartlett,Daven Khana,Andrew Smith,Zakery Baker,Alain Chevalier,Brian Pfleger,Daniel Amador‐Noguez,Judith Simcox
+22 authors
,David Pagliarini
Published
Jan 9, 2024
Show more
Save
TipTip
Document
Download
Flag content
0
TipTip
Save
Document
Download
Flag content

Abstract

Fatty acid β-oxidation (FAO) is a central catabolic pathway with broad implications for organismal health. However, various fatty acids are largely incompatible with standard FAO machinery until they are modified by other enzymes. Included among these are the 4-hydroxy acids (4-HAs)-fatty acids hydroxylated at the 4 (γ) position-which can be provided from dietary intake, lipid peroxidation, and certain drugs of abuse. Here, we reveal that two atypical and poorly characterized acyl-CoA dehydrogenases (ACADs), ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains N-terminal to their ACAD domains that phosphorylate the 4-OH position as a requisite step in the conversion of 4-hydroxyacyl-CoAs into 2-enoyl-CoAs-conventional FAO intermediates. Our ACAD11 cryo-EM structure and molecular modeling reveal a unique binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma while comparable 3- and 5-hydroxy acids remain unchanged. Collectively, this work defines ACAD10 and ACAD11 as the primary gatekeepers of mammalian 4-HA catabolism and sets the stage for broader investigations into the ramifications of aberrant 4-HA metabolism in human health and disease.

Paper PDF

This paper's license is marked as closed access or non-commercial and cannot be viewed on ResearchHub. Visit the paper's external site.