Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas

• Published in: Nature communications 2022-12, Vol.13 (1), p.7637-7637, Article 7637
• Main Authors: Zhang, Haifeng, Li, Busu, Huang, Qunhua, López-Giráldez, Francesc, Tanaka, Yoshiaki, Lin, Qun, Mehta, Sameet, Wang, Guilin, Graham, Morven, Liu, Xinran, Park, In-Hyun, Eichmann, Anne, Min, Wang, Zhou, Jenny Huanjiao
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/51; 13/95; 14/19; 14/28; 14/63; 38/23; 45/91; 631/80/304; 692/308/1426; Angiogenesis; Animals; Arteriovenous Malformations - genetics; Arteriovenous Malformations - metabolism; Blood vessels; Depletion; Extracellular matrix; Gene Expression Regulation; Growth rate; Humanities and Social Sciences; Localization; Membrane Proteins - metabolism; Mice; Mitochondria; Mitochondria - metabolism; multidisciplinary; Mutants; Phosphorylation; Proteins; Receptor, Transforming Growth Factor-beta Type I - genetics; Receptor, Transforming Growth Factor-beta Type I - metabolism; Retina; Science; Science (multidisciplinary); Signal Transduction; Signaling; Smad2 protein; Smad2 Protein - genetics; Smad2 Protein - metabolism; Thickening; Thioredoxin; Thioredoxin 2; Transforming Growth Factor beta - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35262-w

Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here we show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM). Single-cell RNA-seq analyses indicate that retinal ECs from the three mutant mice have increased TGFβ signaling and altered gene expressions associated with vascular maturation and extracellular matrix, correlating with vascular malformation and increased basement membrane thickening in microvesels of mutant retinas. Mechanistic studies suggest that mitochondrial dysfunction from Tfam , Cox10 , or Trx2 depletion induces a mitochondrial localization and MAPKs-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling. Importantly, pharmacological blockade of ALK5 signaling or genetic deficiency of SMAD2 prevented retinal vessel growth retardation and AVM in all three mutant mice. Our studies uncover a novel mechanism whereby mitochondrial dysfunction via the ALK5-SMAD2 signaling induces retinal vascular malformations, and have therapeutic values for the alleviation of angiogenesis-associated human retinal diseases. The role of mitochondrial activity in angiogenesis is not entirely understood. Here, the authors show that mitochondria as a signaling hub and their dysfunction causes augmented TGFβ signaling to induce retinal sprouting retardation and vascular malformations.