1. Histone Deacetylase 3 Couples Mitochondria to Drive IL-1β-Dependent Inflammation by Configuring Fatty Acid Oxidation
- Author
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Qizhen Ye, Xuyan Yang, Zhen Wang, Wenxuan Zhen, Zhexu Chi, Weiwei Yu, Jian Zhang, Fan Yang, Dehang Yang, Mobai Li, Di Wang, Xue Zhang, Kailian Zhang, Hui Fang, Danlu Jiang, Sheng Chen, Xingchen Guo, Hui Lin, and Ting Xu
- Subjects
Adult ,Male ,Protein subunit ,Interleukin-1beta ,Inflammation ,Mitochondrion ,Biology ,Histone Deacetylases ,Oxidative Phosphorylation ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Humans ,Myeloid Cells ,Molecular Biology ,Beta oxidation ,030304 developmental biology ,chemistry.chemical_classification ,Mice, Knockout ,0303 health sciences ,Caspase 1 ,Fatty Acids ,Depolarization ,Cell Biology ,Middle Aged ,HDAC3 ,Lipid Metabolism ,Cell biology ,Mitochondria ,Mice, Inbred C57BL ,Enzyme ,chemistry ,Acetylation ,Female ,Mitochondrial Trifunctional Protein, alpha Subunit ,medicine.symptom ,Oxidation-Reduction ,030217 neurology & neurosurgery - Abstract
Summary Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1β production in macrophages through non-histone deacetylation. In vivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO enzyme, mitochondrial trifunctional enzyme subunit α. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1β-dependent inflammation.
- Published
- 2019