Fig. 8: Lipophagy maintains lymphatic identity and lymphangiogenesis by supplying fatty acids to the mitochondria for fatty acid oxidation and PROX1-mediated gene expression.

The figure depicts the main phenotypes of (left to right) autophagy-proficient LEC (autophagy ON), autophagy-deficient LEC (autophagy OFF), and their rescue with acetate, described in the study. Under homeostatic conditions (left panel), constitutive levels of autophagy favor the turnover of lipid droplets (LDs) in order to supply free fatty acids to the mitochondria and foster fatty acid oxidation (FAO). The actively respiring elongated mitochondria replete acetyl-CoA pools, which is used by the acetyltransferase p300 to acetylate histones at PROX1-target genes. This autophagy-regulated mechanism maintains PROX1-driven expression of lymphatic markers and VEGFR3-mediated lymphangiogenic signaling. When autophagy is compromised (center panel), LDs turnover is impaired causing accumulation of LDS in the cytosol. Under these conditions, the ability of mitochondria to perform FAO is compromised, the mitochondrial network is fragmented and acetyl-CoA levels drop to levels unable to support transcription of PROX1-driven lymphatic gene networks and lymphangiogenesis. This phenotype can be rescued by feeding LEC with the acetyl-CoA precursor acetate (right panel). Acetate rescues mitochondrial morphology and FAO and recovers PROX1-mediated expression of lymphatic genes, thus bypassing the lymphangiogenesis defects caused by genetic loss of autophagy. Image created with Biorender.com.