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Tytuł pozycji:

Absence of retbindin blocks glycolytic flux, disrupts metabolic homeostasis, and leads to photoreceptor degeneration.

Tytuł:
Absence of retbindin blocks glycolytic flux, disrupts metabolic homeostasis, and leads to photoreceptor degeneration.
Autorzy:
Sinha T; Department of Biomedical Engineering, University of Houston, Houston, TX 77204.
Du J; Department of Ophthalmology, West Virginia University, Morgantown, WV 26506.; Department of Biochemistry, West Virginia University, Morgantown, WV 26506.
Makia MS; Department of Biomedical Engineering, University of Houston, Houston, TX 77204.
Hurley JB; Department of Biochemistry, University of Washington, Seattle, WA 98195.
Naash MI; Department of Biomedical Engineering, University of Houston, Houston, TX 77204; .
Al-Ubaidi MR; Department of Biomedical Engineering, University of Houston, Houston, TX 77204; .
Źródło:
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Feb 09; Vol. 118 (6).
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural
Język:
English
Imprint Name(s):
Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms:
Eye Proteins/*genetics
Pyruvate Kinase/*genetics
Retina/*metabolism
Retinal Degeneration/*genetics
Animals ; Citric Acid Cycle/genetics ; Disease Models, Animal ; Eye Proteins/metabolism ; Flavins/metabolism ; Glycolysis/genetics ; Homeostasis ; Humans ; Mice ; Pyruvate Kinase/metabolism ; Retina/pathology ; Retinal Degeneration/metabolism ; Retinal Degeneration/pathology
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Grant Information:
R01 EY026030 United States EY NEI NIH HHS; R01 EY026499 United States EY NEI NIH HHS
Contributed Indexing:
Keywords: flavins; metabolism; metabolomics; retbindin; retinal degeneration
Substance Nomenclature:
0 (Eye Proteins)
0 (Flavins)
0 (RTBDN protein, mouse)
EC 2.7.1.40 (Pkm protein, mouse)
EC 2.7.1.40 (Pyruvate Kinase)
Entry Date(s):
Date Created: 20210202 Date Completed: 20210624 Latest Revision: 20210802
Update Code:
20240104
PubMed Central ID:
PMC8017963
DOI:
10.1073/pnas.2018956118
PMID:
33526685
Czasopismo naukowe
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 13 C-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.
Competing Interests: The authors declare no competing interest.

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