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

Anton Iershov, Ivan Nemazanyy, Chantal Alkhoury, Muriel Girard, Esther Barth, Nicolas Cagnard, Alexandra Montagner, Dominique Chretien, Elena I. Rugarli, Herve Guillou, Mario Pende and Ganna Panasyuk ()
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Anton Iershov: Institut Necker-Enfants Malades (INEM)
Ivan Nemazanyy: Institut Necker-Enfants Malades (INEM)
Chantal Alkhoury: Institut Necker-Enfants Malades (INEM)
Muriel Girard: Institut Necker-Enfants Malades (INEM)
Esther Barth: University of Cologne
Nicolas Cagnard: Université Paris Descartes, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633
Alexandra Montagner: INSERM U1048, Université Paul Sabatier
Dominique Chretien: INSERM UMR1141, Hôpital Robert Debré
Elena I. Rugarli: University of Cologne
Herve Guillou: Université de Toulouse, INRA, ENVT, INP-Purpan, UPS
Mario Pende: Institut Necker-Enfants Malades (INEM)
Ganna Panasyuk: Institut Necker-Enfants Malades (INEM)

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09598-9

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