Universität zu Köln

Iershov, Anton, Nemazanyy, Ivan, Alkhoury, Chantal, Girard, Muriel, Barth, Esther, Cagnard, Nicolas, Montagner, Alexandra ORCID: 0000-0002-4800-5105, Chretien, Dominique, Rugarli, Elena I. ORCID: 0000-0002-5782-1067, Guillou, Herve ORCID: 0000-0002-5363-9081, Pende, Mario ORCID: 0000-0002-7864-8937 and Panasyuk, Ganna (2019). The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPAR alpha. Nat. Commun., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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 (PPAR alpha), a nuclear receptor orchestrating lipid catabolism, is blunted in Vps15-deficient livers. We find PPAR alpha repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagy. Activation of PPAR alpha 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Iershov, Anton UNSPECIFIED UNSPECIFIED UNSPECIFIED Nemazanyy, Ivan UNSPECIFIED UNSPECIFIED UNSPECIFIED Alkhoury, Chantal UNSPECIFIED UNSPECIFIED UNSPECIFIED Girard, Muriel UNSPECIFIED UNSPECIFIED UNSPECIFIED Barth, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Cagnard, Nicolas UNSPECIFIED UNSPECIFIED UNSPECIFIED Montagner, Alexandra UNSPECIFIED orcid.org/0000-0002-4800-5105 UNSPECIFIED Chretien, Dominique UNSPECIFIED UNSPECIFIED UNSPECIFIED Rugarli, Elena I. UNSPECIFIED orcid.org/0000-0002-5782-1067 UNSPECIFIED Guillou, Herve UNSPECIFIED orcid.org/0000-0002-5363-9081 UNSPECIFIED Pende, Mario UNSPECIFIED orcid.org/0000-0002-7864-8937 UNSPECIFIED Panasyuk, Ganna UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-150975
DOI:	10.1038/s41467-019-09598-9
Journal or Publication Title:	Nat. Commun.
Volume:	10
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INSULIN-RESISTANCE; FATTY-ACIDS; LIVER; MUSCLE; METABOLISM; GLUCOSE; PROTEIN; PIK3C3/VPS34; TRANSLATION; EICOSANOIDS Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15097