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

Author

Listed:
  • Odeta Meçe

    (KU Leuven
    VIB Center for Cancer Biology Research)

  • Diede Houbaert

    (KU Leuven
    VIB Center for Cancer Biology Research)

  • Maria-Livia Sassano

    (KU Leuven
    VIB Center for Cancer Biology Research)

  • Tania Durré

    (Liege University)

  • Hannelore Maes

    (KU Leuven)

  • Marco Schaaf

    (KU Leuven
    VIB Center for Cancer Biology Research)

  • Sanket More

    (KU Leuven
    VIB Center for Cancer Biology Research)

  • Maarten Ganne

    (KU Leuven
    VIB Center for Cancer Biology Research)

  • Melissa García-Caballero

    (VIB Center for Cancer Biology, VIB
    KU Leuven)

  • Mila Borri

    (VIB Center for Cancer Biology, VIB
    KU Leuven)

  • Jelle Verhoeven

    (KU Leuven
    VIB Center for Cancer Biology Research)

  • Madhur Agrawal

    (KU Leuven
    VIB Center for Cancer Biology Research)

  • Kathryn Jacobs

    (KU Leuven
    KU Leuven
    Laboratory for Tumor Microenvironment and Therapeutic Resistance VIB Center for Cancer Biology, VIB)

  • Gabriele Bergers

    (KU Leuven
    Laboratory for Tumor Microenvironment and Therapeutic Resistance VIB Center for Cancer Biology, VIB)

  • Silvia Blacher

    (Liege University)

  • Bart Ghesquière

    (KU Leuven)

  • Mieke Dewerchin

    (VIB Center for Cancer Biology, VIB
    KU Leuven)

  • Johan V. Swinnen

    (KU Leuven)

  • Stefan Vinckier

    (VIB Center for Cancer Biology, VIB
    KU Leuven)

  • María S. Soengas

    (Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO))

  • Peter Carmeliet

    (VIB Center for Cancer Biology, VIB
    KU Leuven)

  • Agnès Noël

    (Liege University)

  • Patrizia Agostinis

    (KU Leuven
    VIB Center for Cancer Biology Research)

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.

Suggested Citation

  • 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, 2022. "Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30490-6
    DOI: 10.1038/s41467-022-30490-6
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