Dataset Information

Serine supplementation suppresses hypoxia-induced pathological retinal angiogenesis

ABSTRACT: Pathological retinal angiogenesis with irregular and fragile vessels (also termed as neovascularization, a response to hypoxia and dysmetabolism) is a leading cause of vision loss in all age groups driven in part by unmet metabolic demand from retinal neurons. Sustaining neural retinal metabolism with an adequate nutrient supply may prevent vision-threatening neovascularization. Low circulating serine levels are associated with neovascularization in macular telangiectasia and altered serine/glycine metabolism is suggested in retinopathy of prematurity. Here we assessed the role of serine metabolism in suppressing hypoxia-driven retinal neovascularization in mice. Systemic serine supplementation decreased, and dietary serine/glycine deficiency worsened retinal neovascularization. Fatty acid oxidation was essential in mediating serine protective effects and serine also increased the levels of phosphatidylcholine, the most abundant phospholipids in the retina. Exogenous serine increased abundance of proteins involved in oxidative phosphorylation in total retinas, as well as increased expression of mitochondrial respiration-related genes and decreased expression of pro-angiogenic genes in rod photoreceptor cluster. Pharmaceutical inhibition of mitochondrial energy production largely attenuated serine suppression of retinal neovascularization. Our data suggested that increasing serine is a potential therapeutic approach for neovascular eye diseases by enhancing retinal mitochondrial function and lipid metabolism to suppress driving factors for uncontrolled angiogenesis.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Retina

SUBMITTER: Zhongjie Fu

LAB HEAD: Zhongjie Fu

PROVIDER: PXD056490 | Pride | 2025-05-07

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	41_HY_Jax_P17_Control_vs_Serine.mzML	Mzml
	41_HY_Jax_P17_Control_vs_Serine.mzid.gz	Mzid
	41_HY_Jax_P17_Control_vs_Serine.pdResult	Other
	41_HY_Jax_P17_PBS_1.raw	Raw
	41_HY_Jax_P17_PBS_2.raw	Raw

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Publications

Serine supplementation suppresses hypoxia-induced pathological retinal angiogenesis.

Yagi Hitomi H Qiu Chenxi C Zeng Yan Y Boeck Myriam M Nian Shen S Chen Chuck T CT Harman Jarrod C JC Kasai Taku T Lee Jeff J Hirst Victoria V Neilsen Katherine K Wang Chaomei C Bora Kiran K Maurya Meenakshi M Rodrick Tori T Grumbine Matthew M Yang Yuelin Y Hua Zhanqing Z Sweet Ian R IR Singh Sasha A SA Aikawa Masanori M Chen Jing J Fu Zhongjie Z

Theranostics 20250409 11

<b>Rationale</b>: Pathological retinal angiogenesis with irregular and fragile vessels (also termed neovascularization, a response to hypoxia and dysmetabolism) is a leading cause of vision loss in all age groups. This process is driven in part through the energy deficiency in retinal neurons. Sustaining neural retinal metabolism with adequate nutrient supply may help prevent vision-threatening neovascularization. Low circulating serine levels are associated with neovascularization in macular te ...[more]

PMID: 40303351

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Project description:Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here, we investigate the angiogenic functions of three separate nuclear genes that encode for mitochondrial proteins, including mitochondrial transcriptional factor (TFAM), respiratory complex IV component (COX10), and a mitochondrial redox protein thioredoxin 2 (TRX2), which are responsible for distinct mitochondrial functions. We aim to investigate if mitochondrial activities regulate common endothelial cell (EC) signaling pathways during angiogenesis. The silencing of Tfam, Cox10, or Trx2 in an in vitro 3D sprouting assay attenuates EC sprouting, which correlated with reduced EC proliferation but not with ROS generation or EC apoptosis. Mice with an inducible deletion of Tfam, Cox10, or Trx2 exhibit retarded retinal vessel growth without penetration into the deep plexi at early ages (P5-P12). The three mutant mice develop arteriovenous malformations (AVM) with microaneurysm formation in the microvessels at advanced ages (P12-P30); the hypovasculature and microaneurysm phenotypes resemble that of aged human retinas and human primitive retinal vascular abnormalities such as Coats’ disease, Leber’s military aneurysms and familial exudative vitreoretinopathy. Single-cell RNA-seq analyses of retinal ECs suggest that the three mutant mice have common EC clusters with reduced gene expressions in anion transporters, actin organization, extracellular matrix, and angiogenesis. These EC clusters also have increased gene expressions in endothelial-mesenchymal transition and arterial markers, correlating with enhanced TGFbR signaling in Tfam, Cox10, or Trx2-deficient mice. Importantly, pharmacological blockade by TGFbR inhibitors attenuated retinal vessel growth retardation and AVM formation in all three mutant mice. Our study demonstrates that mitochondrial dysfunction induces TGF-b receptor-mediated arteriovenous malformations and microaneurysm formation in mouse retinas, and provide a novel model and therapeutic intervention for human primitive retinal vascular abnormalities, which are characterized by retinal vascular malformations and are associated with many pathological complications such as diabetes and hypertension that can result in vision loss.