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

Anton Iershov (1) , Ivan Nemazanyy (1, 2) , Chantal Alkhoury (1) , Muriel Girard (1, 3) , Esther Barth (4) , Nicolas Cagnard (5) , Alexandra Montagner (6) , Dominique Chretien (2, 7) , Elena I. Rugarli (4) , Hervé Guillou (8) , Mario Pende (1) , Ganna Panasyuk (1)

1 Hôpital Necker - Enfants Malades [AP-HP]
2 INSERM - Institut National de la Santé et de la Recherche Médicale
3 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
4 University of Cologne
5 SFR Necker - UMS 3633 / US24 - Structure Fédérative de Recherche Necker
6 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
7 UPD7 - Université Paris Diderot - Paris 7
8 ToxAlim-TIM - Toxicologie Intégrative & Métabolisme

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.

Domaines: Sciences du Vivant [q-bio]

Anton Iershov, Ivan Nemazanyy, Chantal Alkhoury, Muriel Girard, Esther Barth, et al.. The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα. Nature Communications, 2019, 10 (1), 18 p. ⟨10.1038/s41467-019-09598-9⟩. ⟨hal-02622186⟩