Histone Deacetylase 3 Couples Mitochondria to Drive IL-1β-Dependent Inflammation by Configuring Fatty Acid Oxidation.

Abstract

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.

• Authors: Zhexu Chi, Sheng Chen, Ting Xu, Wenxuan Zhen, Weiwei Yu, Danlu Jiang, Xingchen Guo, Zhen Wang, Kailian Zhang, Mobai Li, Jian Zhang, Hui Fang, Dehang Yang, Qizhen Ye, Xuyan Yang, Hui Lin, Fan Yang, Xue Zhang, Di Wang
• Journal: Molecular cell (Mol Cell) Vol. 80 Issue 1 Pg. 43-58.e7 (10 01 2020) ISSN: 1097-4164 [Electronic] United States
• PMID: 32937100 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Fatty Acids
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Mitochondrial Trifunctional Protein, alpha Subunit
• Caspase 1
• Histone Deacetylases
• histone deacetylase 3
• Hadha protein, mouse

Topics

• Adult
• Animals
• Caspase 1 (metabolism)
• Fatty Acids (metabolism)
• Female
• Histone Deacetylases (metabolism)
• Humans
• Inflammation (metabolism, pathology)
• Interleukin-1beta (metabolism)
• Lipid Metabolism
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Mitochondria (metabolism, ultrastructure)
• Mitochondrial Trifunctional Protein, alpha Subunit (metabolism)
• Myeloid Cells (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Oxidation-Reduction
• Oxidative Phosphorylation
• Young Adult