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

Odeta Meçe, Diede Houbaert, Maria-Livia Sassano, Tania Durré, Hannelore Maes, Marco Schaaf, Sanket More, Maarten Ganne, Melissa García-Caballero, Mila Borri, Jelle Verhoeven, Madhur Agrawal, Kathryn Jacobs, Gabriele Bergers, Silvia Blacher, Bart Ghesquière, Mieke Dewerchin, Johan V. Swinnen, Stefan Vinckier, María S. Soengas, Peter Carmeliet, Agnès Noël and Patrizia Agostinis ()
Additional contact information
Odeta Meçe: KU Leuven
Diede Houbaert: KU Leuven
Maria-Livia Sassano: KU Leuven
Tania Durré: Liege University
Hannelore Maes: KU Leuven
Marco Schaaf: KU Leuven
Sanket More: KU Leuven
Maarten Ganne: KU Leuven
Melissa García-Caballero: VIB Center for Cancer Biology, VIB
Mila Borri: VIB Center for Cancer Biology, VIB
Jelle Verhoeven: KU Leuven
Madhur Agrawal: KU Leuven
Kathryn Jacobs: KU Leuven
Gabriele Bergers: KU Leuven
Silvia Blacher: Liege University
Bart Ghesquière: KU Leuven
Mieke Dewerchin: VIB Center for Cancer Biology, VIB
Johan V. Swinnen: KU Leuven
Stefan Vinckier: VIB Center for Cancer Biology, VIB
María S. Soengas: Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO)
Peter Carmeliet: VIB Center for Cancer Biology, VIB
Agnès Noël: Liege University
Patrizia Agostinis: KU Leuven

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30490-6

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