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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Chi Z,Chen S,Xu T,Zhen W,Yu W,Jiang D,Guo X,Wang Z,Zhang K,Li M,Zhang J,Fang H,Yang D,Ye Q,Yang X,Lin H,Yang F,Zhang X,Wang D

doi

10.1016/j.molcel.2020.08.015

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

43-58.e7

issue

1

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(20)30578-5

journal_volume

80

pub_type

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