Journal Article

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

Pende, Mario, Institut National de la Santé et de la Recherche Médicale (INSERM), Chretien, Dominique, Panasyuk, Ganna, Nemazanyy, Ivan, Cagnard, Nicolas, Girard, Muriel, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC) ; Université Toulouse III - Paul Sabatier (UT3) ; Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Iershov, Anton, ANR-16-CE14-0029,NUTRISENSPIK,Déterminants moléculaires de l'homéostasie hépatique nutritive, Rugarli, Elena I, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24) ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Barth, Esther, Alkhoury, Chantal, Guillou, Hervé, Hôpital Necker - Enfants Malades [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Toxicologie

2019

Overview

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.

• Publisher: Nature Publishing Group,CCSD,Nature Publishing Group UK,Nature Portfolio
• Subject: 1-Phosphatidylinositol 3-kinase / 101/58 / 13 / 13/1 / 13/106 / 13/109 / 13/44 / 13/95 / 14 / 14/28 / 38 / 631/443/319 / 631/80/39 / 631/80/86/388 / 64/110 / 64/60 / 82/29 / 96/35 / Animals / Autophagy / Autophagy - drug effects / Autophagy - genetics / Autophagy - physiology / Catabolism / Deactivation / Depletion / Fatty acids / Fenofibrate - pharmacology / Gene Expression Regulation - drug effects / HEK293 Cells / Hepatocytes / Hepatocytes - cytology / Hepatocytes - drug effects / Hepatocytes - metabolism / Histone deacetylase / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Histone Deacetylases - physiology / Humanities and Social Sciences / Humans / Inactivation / Kinases / Life Sciences / Lipid metabolism / Lipid Metabolism - drug effects / Lipid peroxidation / Lipids / Liver / Lysosomes / Male / Metabolism / Mice / Mice, Knockout / Mitochondria / Mitochondria - metabolism / multidisciplinary / Nuclear Receptor Co-Repressor 1 - genetics / Nuclear Receptor Co-Repressor 1 - metabolism / Nuclear Receptor Co-Repressor 1 - physiology / Nuclear receptors / Nutrient availability / Oxidation / Phagocytosis / Phosphatidylinositol 3-Kinases - genetics / Phosphatidylinositol 3-Kinases - metabolism / Phosphatidylinositol 3-Kinases - physiology / PPAR alpha - metabolism / Receptors / Repressors / Science / Science (multidisciplinary) / Transcription / Transcription, Genetic - drug effects / Vacuolar Sorting Protein VPS15 - genetics / Vacuolar Sorting Protein VPS15 - metabolism / Vacuolar Sorting Protein VPS15 - physiology
• ISBN: 0004634722000