Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 05 2022
19 05 2022
Historique:
received:
25
02
2022
accepted:
29
04
2022
entrez:
19
5
2022
pubmed:
20
5
2022
medline:
24
5
2022
Statut:
epublish
Résumé
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
Identifiants
pubmed: 35589749
doi: 10.1038/s41467-022-30490-6
pii: 10.1038/s41467-022-30490-6
pmc: PMC9120506
doi:
Substances chimiques
Fatty Acids
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2760Informations de copyright
© 2022. The Author(s).
Références
Sci Adv. 2021 Apr 30;7(18):
pubmed: 33931446
Circ Res. 2022 Jan 7;130(1):24-26
pubmed: 34995134
Nat Rev Cancer. 2014 Mar;14(3):159-72
pubmed: 24561443
J Clin Invest. 2011 Aug;121(8):2984-92
pubmed: 21765212
Development. 2014 Feb;141(3):538-47
pubmed: 24449835
J Clin Invest. 2010 May;120(5):1694-707
pubmed: 20364082
Int J Cancer. 2015 Oct 1;137(7):1539-48
pubmed: 25784292
Nat Metab. 2019 Jul;1(7):666-675
pubmed: 32694649
EMBO J. 2017 Jun 14;36(12):1688-1706
pubmed: 28465321
Nat Med. 2011 Nov 07;17(11):1371-80
pubmed: 22064427
Invest Ophthalmol Vis Sci. 2013 May 03;54(5):3082-93
pubmed: 23580490
Genes Dev. 2014 Oct 1;28(19):2175-87
pubmed: 25274728
Nature. 2008 Dec 4;456(7222):643-7
pubmed: 18931657
Trends Biochem Sci. 2020 Apr;45(4):347-364
pubmed: 32044127
Nature. 2004 Dec 23;432(7020):1032-6
pubmed: 15525940
Nature. 2017 Feb 2;542(7639):49-54
pubmed: 28024299
Biochemistry. 2013 Aug 27;52(34):5746-59
pubmed: 23862699
Nature. 2020 Sep;585(7823):113-118
pubmed: 32814895
Nat Rev Mol Cell Biol. 2020 Apr;21(4):204-224
pubmed: 32071438
Cell Metab. 2018 Apr 3;27(4):869-885.e6
pubmed: 29617645
Cell. 2014 Dec 4;159(6):1263-76
pubmed: 25480292
Genes Dev. 2017 Aug 15;31(16):1615-1634
pubmed: 28947496
EMBO J. 2002 Apr 2;21(7):1505-13
pubmed: 11927535
Magn Reson Med. 2016 Nov 10;77(1):11
pubmed: 27851883
Dev Cell. 2021 Feb 22;56(4):406-426
pubmed: 33621491
Nat Commun. 2019 Apr 5;10(1):1567
pubmed: 30952864
Autophagy. 2018;14(6):1060-1071
pubmed: 29909716
Mol Biol Cell. 2001 Aug;12(8):2245-56
pubmed: 11514614
Genes Dev. 2010 Apr 1;24(7):696-707
pubmed: 20360386
Exp Eye Res. 2009 Aug;89(2):274-6
pubmed: 19285069
Nat Rev Mol Cell Biol. 2019 Mar;20(3):137-155
pubmed: 30523332
J Biol Chem. 2011 Sep 2;286(35):30624-30635
pubmed: 21757691
Cell Metab. 2018 Apr 3;27(4):886-897.e4
pubmed: 29617646
Nature. 2009 Apr 30;458(7242):1131-5
pubmed: 19339967
J Clin Invest. 2004 Apr;113(7):1040-50
pubmed: 15057311
EMBO J. 2019 Sep 2;38(17):e100938
pubmed: 31328803
Nature. 2015 Apr 9;520(7546):192-197
pubmed: 25830893
Trends Mol Med. 2013 Jul;19(7):428-46
pubmed: 23714574
Cell Death Differ. 2019 Mar;26(4):665-679
pubmed: 30692642
Dev Cell. 2015 Mar 23;32(6):678-92
pubmed: 25752962
Mol Cell Biochem. 2007 May;299(1-2):67-73
pubmed: 16645726
Exp Cell Res. 2004 Jul 15;297(2):415-23
pubmed: 15212944
J Cell Biol. 2019 Oct 7;218(10):3320-3335
pubmed: 31391210
Dev Cell. 2017 Jul 10;42(1):9-21.e5
pubmed: 28697336
J Cell Sci. 2020 May 22;133(10):
pubmed: 32501285
Biochim Biophys Acta. 2013 Oct;1832(10):1605-12
pubmed: 23669346
Cancer Cell. 2014 Aug 11;26(2):190-206
pubmed: 25117709
Angiogenesis. 2018 Aug;21(3):425-532
pubmed: 29766399
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8868-73
pubmed: 12070340
Cell Metab. 2011 Jun 8;13(6):655-67
pubmed: 21641547
J Mol Biol. 2018 Oct 19;430(21):3922-3941
pubmed: 30089235
Cell Metab. 2018 Dec 4;28(6):881-894.e13
pubmed: 30146488
Cell Rep. 2016 Nov 1;17(6):1463-1472
pubmed: 27806287
Autophagy. 2017 Oct 3;13(10):1629-1647
pubmed: 28813167
Circ Res. 2015 Jan 30;116(3):480-8
pubmed: 25634971
Genes Dev. 2008 Dec 1;22(23):3282-91
pubmed: 19056883
Nat Protoc. 2011 Jun;6(6):817-26
pubmed: 21637201
Yale J Biol Med. 2019 Sep 20;92(3):435-452
pubmed: 31543707
J Vis Exp. 2014 Aug 16;(90):
pubmed: 25177860
Nat Metab. 2019 Jan;1(1):158-171
pubmed: 31106291