Heinken Almut, Asara John M, Gnanaguru Gopalan, Singh Charandeep
Inserm UMRS 1256 NGERE, University of Lorraine, Nancy, France.
Division of Signal Transduction/Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA.
Commun Biol. 2025 Jan 9;8(1):25. doi: 10.1038/s42003-024-07394-w.
Activation of anaplerosis takes away glutamine from the biosynthetic pathways to the energy-producing TCA cycle. Especially, induction of hyperoxia driven anaplerosis in neurovascular tissues such as the retina during early stages of development could deplete biosynthetic precursors from newly proliferating endothelial cells impeding physiological angiogenesis and leading to vasoobliteration. Using an oxygen-induced retinopathy (OIR) mouse model, we investigated the metabolic differences between OIR-resistant BALB/cByJ and OIR susceptible C57BL/6J strains at system levels to understand the molecular underpinnings that potentially contribute to hyperoxia-induced vascular abnormalities in the neural retina. Our systems level in vivo RNA-seq, proteomics, and lipidomic profiling and ex-vivo retinal explant studies show that the medium-chain fatty acids serves as an alternative source to feed the TCA cycle. Our findings strongly implicate that medium-chain fatty acids could suppress glutamine-fueled anaplerosis and ameliorate hyperoxia-induced vascular abnormalities in conditions such as retinopathy of prematurity.
回补反应的激活会将谷氨酰胺从生物合成途径中夺走，转而进入产生能量的三羧酸循环。特别是在发育早期，如视网膜等神经血管组织中，高氧驱动的回补反应的诱导可能会耗尽新增殖的内皮细胞中的生物合成前体，从而阻碍生理性血管生成并导致血管闭塞。我们使用氧诱导视网膜病变（OIR）小鼠模型，在系统水平上研究了抗OIR的BALB/cByJ品系和易患OIR的C57BL/6J品系之间的代谢差异，以了解可能导致神经视网膜中高氧诱导血管异常的分子基础。我们的体内RNA测序、蛋白质组学和脂质组学分析以及体外视网膜外植体研究表明，中链脂肪酸可作为另一种为三羧酸循环供能的来源。我们的研究结果有力地表明，中链脂肪酸可以抑制谷氨酰胺驱动的回补反应，并改善诸如早产儿视网膜病变等情况下高氧诱导的血管异常。
