Available online 31 March 2023, 101717
Author links open overlay panel, , , , , , , , Highlights•AhR has diverse roles in normal liver physiology and pathology.
•AhR inhibition suppresses the mitophagy process in the fasted liver, which leads to mitochondrial dysfunction.
•A mitophagy receptor BNIP3 is a new direct target of AhR to modulate mitochondria homeostasis.
AbstractBackground & AimsMitophagy removes damaged mitochondria to maintain cellular homeostasis. Aryl hydrocarbon receptor (AhR) expression in the liver plays a crucial role in supporting normal liver functions, but its impact on mitochondrial function is unclear. Here, we identified a new role of AhR in the regulation of mitophagy to control hepatic energy homeostasis.
Approach &ResultsTranscriptomic analysis indicated that mitochondria-related gene sets were dysregulated in AhR knockout (KO) liver. In both primary mouse hepatocytes and AML12 hepatocyte cell lines, AhR inhibition strongly suppressed mitochondrial respiration rate and substrate utilization. AhR inhibition also blunted the fasting response of several essential autophagy genes and the mitophagy process. We further identified BCL2 interacting protein 3 (BNIP3), a mitophagy receptor that senses nutrient stress, as an AhR target gene. AhR is directly recruited to the Bnip3 genomic locus, and Bnip3 transcription was enhanced by AhR endogenous ligand treatment in wild-type liver and abolished entirely in AhR KO liver. Mechanistically, overexpression of Bnip3 in AhR knockdown cells mitigated the production of mitochondrial reactive oxygen species (ROS) and restored functional mitophagy.
ConclusionsAhR regulation of the mitophagy receptor BNIP3 coordinates hepatic mitochondrial function. Loss of AhR induces mitochondrial ROS production and impairs mitochondrial respiration. These findings provide new insight into how endogenous AhR governs hepatic mitochondrial homeostasis.
Keywordsmax 5): mitophagy
autophagy
reactive oxygen species
BNIP3
kynurenine
AbbreviationsAhRaryl hydrocarbon receptor
BNIP3Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3
BNIP3LBCL2/adenovirus E1B 19 kDa protein-interacting protein 3 like
ChIPchromatin immunoprecipitation
GEOgene expression omnibus
GSEAgene set enrichment analysis
NESnormalized enrichment score
OCRoxygen consumption rate
ROSreactive oxygen species
TCDD2,3,7,8-tetrachlorodibenzo-p-dioxin
© 2023 Published by Elsevier GmbH.
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