ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism
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 ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma and females are susceptible to body weight and fat gain, concurrent with decreased adipocyte differentiation and adipokine expression. Collectively, we present that ACAD10 and ACAD11 are the primary gatekeepers of mammalian 4-HA catabolism.
Authors
- Judith Simcox (ORCID: https://orcid.org/0000-0001-7350-6342)
- Luciano A. Abriata (ORCID: https://orcid.org/0000-0003-3087-8677)
- Daniel Amador‐Noguez (ORCID: https://orcid.org/0000-0002-3568-3070)
- Alana Caldwell (ORCID: https://orcid.org/0009-0008-8613-104X)
- David J. Pagliarini (ORCID: https://orcid.org/0000-0002-0001-0087)
- Raghav Jain (ORCID: https://orcid.org/0000-0002-1284-6762)
- Gina Wade (ORCID: https://orcid.org/0009-0000-1773-1393)
- Edrees H. Rashan (ORCID: https://orcid.org/0000-0002-3882-6655)
- Zakery N. Baker (ORCID: https://orcid.org/0000-0002-0503-9460)
- Peng Yuan (ORCID: https://orcid.org/0000-0002-5660-225X)
- Matteo Dal Peraro (ORCID: https://orcid.org/0000-0002-2973-3975)
- Daven B. Khana (ORCID: https://orcid.org/0000-0002-8081-3436)
- Brian F. Pfleger (ORCID: https://orcid.org/0000-0002-9232-9959)
- Patrick Forny (ORCID: https://orcid.org/0000-0003-1877-2976)
- Taylor W. Cook (ORCID: https://orcid.org/0000-0003-1616-650X)
- Jingying Zhang (ORCID: https://orcid.org/0009-0005-6130-2779)
- Andrew J. H. Smith (ORCID: https://orcid.org/0000-0002-4327-5886)
- Abigail K. Bartlett
- Autumn Chevalier
Institutions
- SIB Swiss Institute of Bioinformatics (CH)
- Howard Hughes Medical Institute (US)
- University of Wisconsin–Madison (US)
- Washington University in St. Louis (US)
- Morgridge Institute for Research (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Structural & Molecular Biology
- Published
- 2025-06-19
- DOI
- https://doi.org/10.1038/s41594-025-01596-4
- Citations
- 5
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 4.03