气候变化领域集成服务门户(CCPortal): Absence of retbindin blocks glycolytic flux, disrupts metabolic homeostasis, and leads to photoreceptor degeneration

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DOI	10.1073/pnas.2018956118
	Absence of retbindin blocks glycolytic flux, disrupts metabolic homeostasis, and leads to photoreceptor degeneration
	Sinha T.; Du J.; Makia M.S.; Hurley J.B.; Naash M.I.; Al-Ubaidi M.R.
发表日期	2021
ISSN	00278424
卷号	118 期号:6
英文摘要	We previously reported a model of progressive retinal degeneration resulting from the knockout of the retina-specific riboflavin binding protein, retbindin (Rtbdn−/−). We also demonstrated a reduction in neural retinal flavins as a result of the elimination of RTBDN. Given the role of flavins in metabolism, herein we investigated the underlying mechanism of this retinal degeneration by performing metabolomic analyses on predegeneration at postnatal day (P) 45 and at the onset of functional degeneration in the P120 retinas. Metabolomics of hydrophilic metabolites revealed that individual glycolytic products accumulated in the P45 Rtbdn−/− neural retinas along with the elevation of pentose phosphate pathway, while TCA cycle intermediates remained unchanged. This was confirmed by using 13C-labeled flux measurements and immunoblotting, revealing that the key regulatory step of phosphoenolpyruvate to pyruvate was inhibited via down-regulation of the tetrameric pyruvate kinase M2 (PKM2). Separate metabolite assessments revealed that almost all intermediates of acylcarnitine fatty acid oxidation, ceramides, sphingomyelins, and multiple toxic metabolites were significantly elevated in the predegeneration Rtbdn−/− neural retina. Our data show that lack of RTBDN, and hence reduction in flavins, forced the neural retina into repurposing glucose for free-radical mitigation over ATP production. However, such sustained metabolic reprogramming resulted in an eventual metabolic collapse leading to neurodegeneration. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Flavins; Metabolism; Metabolomics; Retbindin; Retinal degeneration
语种	英语
scopus关键词	acylcarnitine; carbon 13; ceramide; free radical; pentose phosphate; phosphoenolpyruvate; pyruvate kinase; pyruvic acid; retbindin; riboflavin binding protein; riboflavin derivative; sphingomyelin; tetrameric pyruvate kinase M2; tricarboxylic acid; unclassified drug; animal experiment; animal tissue; Article; cell cycle; controlled study; down regulation; drug repositioning; fatty acid oxidation; glycolysis; glycolytic flux; homeostasis; hydrophilicity; immunoblotting; metabolic regulation; metabolite; metabolomics; mouse; nonhuman; nuclear reprogramming; perinatal period; photoreceptor; priority journal; protein depletion; retina degeneration; retinal neuroepithelial layer; Rtbdn gene
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180727
作者单位	Department of Biomedical Engineering, University of Houston, Houston, TX 77204, United States; Department of Ophthalmology, West Virginia University, Morgantown, WV 26506, United States; Department of Biochemistry, West Virginia University, Morgantown, WV 26506, United States; Department of Biochemistry, University of Washington, Seattle, WA 98195, United States
推荐引用方式 GB/T 7714	Sinha T.,Du J.,Makia M.S.,et al. Absence of retbindin blocks glycolytic flux, disrupts metabolic homeostasis, and leads to photoreceptor degeneration[J],2021,118(6).
APA	Sinha T.,Du J.,Makia M.S.,Hurley J.B.,Naash M.I.,&Al-Ubaidi M.R..(2021).Absence of retbindin blocks glycolytic flux, disrupts metabolic homeostasis, and leads to photoreceptor degeneration.Proceedings of the National Academy of Sciences of the United States of America,118(6).
MLA	Sinha T.,et al."Absence of retbindin blocks glycolytic flux, disrupts metabolic homeostasis, and leads to photoreceptor degeneration".Proceedings of the National Academy of Sciences of the United States of America 118.6(2021).