Journal Article

Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis

Schaaf, Marco, Ghesquière, Bart, Bergers, Gabriele, Swinnen, Johan V., Verhoeven, Jelle, Dewerchin, Mieke, Soengas, María S., Ganne, Maarten, Houbaert, Diede, Vinckier, Stefan, García-Caballero, Melissa, Agrawal, Madhur, Noël, Agnès, Maes, Hannelore, More, Sanket, Borri, Mila, Sassano, Maria-Livia, Blacher, Silvia, Carmeliet, Peter, Agostinis, Patrizia, Meçe, Odeta, Durré, Tania, Jacobs, Kathryn

2022

Overview

Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs responses to VEGF-C and injury-driven corneal lymphangiogenesis. Autophagy loss in LEC compromises the expression of main effectors of LEC identity, like VEGFR3, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in vitro and in vivo. When lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation, acetyl-CoA/CoA ratio and expression of lymphangiogenic PROX1 target genes are dwindled. Enforcing mitochondria fusion by silencing dynamin-related-protein 1 (DRP1) in autophagy-deficient LEC fails to restore LDs turnover and lymphatic gene expression, whereas supplementing the fatty acid precursor acetate rescues VEGFR3 levels and signaling, and lymphangiogenesis in LEC-Atg5 −/− mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that safeguards LEC responsiveness to lymphangiogenic mediators and lymphangiogenesis. Autophagy is essential to endothelial cell homeostasis. Here the authors show that lipophagy in LEC supports fatty acid oxidation to sustain a mitochondrial-Prox1 gene expression circuit and promote response of LEC to lymphangiogenic mediators.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/31 / 13/51 / 13/89 / 14/1 / 14/19 / 14/28 / 14/34 / 14/5 / 14/63 / 38/88 / 64/60 / 692/308 / 692/4017 / 82/1 / 82/29 / 82/58 / 82/80 / 96/2 / Acetic acid / Animals / Autophagy / Autophagy - genetics / Biochemistry, Genetics and Molecular Biology (all) / Chemistry (all) / Circuits / Cornea / Droplets / Dynamin / Endothelial Cells / Endothelial Cells - metabolism / Fatty Acids / Fatty Acids - metabolism / Gene expression / General Biochemistry, Genetics and Molecular Biology / General Chemistry / General Physics and Astronomy / Genes / Homeostasis / Human health sciences / Humanities and Social Sciences / Lipid Droplets / Lipid Droplets - metabolism / Lipids / Lymphangiogenesis / Lymphangiogenesis - genetics / Lymphatic Vessels / Lymphatic Vessels - metabolism / Mice / Mitochondria / Multidisciplinary / Oncologie / Oncology / Oxidation / Physics and Astronomy (all) / Prox1 gene / Science / Science (multidisciplinary) / Sciences de la santé humaine / Transcription Factors / Transcription Factors - metabolism / Vascular endothelial growth factor / Vascular endothelial growth factor receptors