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Nat Commun. 2019 Apr 5;10(1):1566. doi: 10.1038/s41467-019-09598-9.

The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα.

Author information

1
Institut Necker-Enfants Malades (INEM), 75014, Paris, France.
2
INSERM U1151/CNRS UMR 8253, 75014, Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, 75006, Paris, France.
4
Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, 75014, Paris, France.
5
Pediatric Hepatology Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
6
Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674, Cologne, Germany.
7
Plateforme Bio-informatique, Université Paris Descartes, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Paris, 75015, France.
8
INSERM U1048, Université Paul Sabatier, Toulouse, 31432, France.
9
INSERM UMR1141, Hôpital Robert Debré, Paris, 75019, France.
10
Université Paris 7, Faculté de Médecine Denis Diderot, Paris, 75019, France.
11
Toxalim, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, 31027, France.
12
Institut Necker-Enfants Malades (INEM), 75014, Paris, France. ganna.panasyuk@inserm.fr.
13
INSERM U1151/CNRS UMR 8253, 75014, Paris, France. ganna.panasyuk@inserm.fr.
14
Université Paris Descartes, Sorbonne Paris Cité, 75006, Paris, France. ganna.panasyuk@inserm.fr.

Abstract

The class 3 phosphoinositide 3-kinase (PI3K) is required for lysosomal degradation by autophagy and vesicular trafficking, assuring nutrient availability. Mitochondrial lipid catabolism is another energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, the class 3 PI3K contribution to this regulation is unknown. We show that liver-specific inactivation of Vps15, the essential regulatory subunit of the class 3 PI3K, elicits mitochondrial depletion and failure to oxidize fatty acids. Mechanistically, transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor orchestrating lipid catabolism, is blunted in Vps15-deficient livers. We find PPARα repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagy. Activation of PPARα or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15-deficient hepatocytes. These findings reveal roles for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.

PMID:
30952952
PMCID:
PMC6451001
DOI:
10.1038/s41467-019-09598-9
[Indexed for MEDLINE]
Free PMC Article

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