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Odd-Chain Dicarboxylic Acid Feeding Produces a Glutaric Aciduria Type 1-Like Metabolic Signature in Mice.

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Τίτλος: Odd-Chain Dicarboxylic Acid Feeding Produces a Glutaric Aciduria Type 1-Like Metabolic Signature in Mice.
Συγγραφείς: Richert AC; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Zhang Y; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Bharathi SS; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Hernandez A; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Dodatko T; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Bons J; The Buck Institute for Research on Aging, Novato, California, USA., Roundtree KE; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Stauffer B; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Yu C; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Schilling B; The Buck Institute for Research on Aging, Novato, California, USA., Houten SM; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Goetzman ES; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Πηγή: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2025 Nov 15; Vol. 39 (21), pp. e71215.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Federation of American Societies for Experimental Biology Country of Publication: United States NLM ID: 8804484 Publication Model: Print Cited Medium: Internet ISSN: 1530-6860 (Electronic) Linking ISSN: 08926638 NLM ISO Abbreviation: FASEB J Subsets: MEDLINE
Imprint Name(s): Publication: 2020- : [Bethesda, Md.] : Hoboken, NJ : Federation of American Societies for Experimental Biology ; Wiley
Original Publication: [Bethesda, Md.] : The Federation, [c1987-
Ιατρικοί όροι (MeSH): Amino Acid Metabolism, Inborn Errors*/metabolism , Amino Acid Metabolism, Inborn Errors*/pathology , Glutaryl-CoA Dehydrogenase*/deficiency , Glutaryl-CoA Dehydrogenase*/metabolism , Dicarboxylic Acids*/metabolism , Dicarboxylic Acids*/administration & dosage , Brain Diseases, Metabolic*/metabolism , Brain Diseases, Metabolic*/chemically induced , Brain Diseases, Metabolic*/pathology, Glutarates/metabolism ; Mitochondria/metabolism ; Peroxisomes/metabolism ; Animals ; Mice ; Male ; Mice, Inbred C57BL
Περίληψη: Glutaric aciduria type-1 (GA1) is an inherited mitochondrial neurometabolic disorder with a poorly understood pathogenesis and unmet medical needs. GA1 can be diagnosed via its hallmark biochemical signature consisting of glutaric aciduria, 3-hydroxyglutaric aciduria, and increased plasma glutarylcarnitine. These glutaryl-CoA-derived metabolites are thought to originate solely in the mitochondria. Here, we demonstrate that wild-type mice fed an 11-carbon odd-chain dicarboxylic acid (undecanedioic acid, DC11) recreate the biochemical phenotype of GA1. Odd-chain dicarboxylic acids like DC11 are not present in food but can arise from several endogenous processes, such as lipid peroxidation and fatty acid ω-oxidation. DC11 is chain-shortened in peroxisomes to glutaryl (DC5)-CoA, which then gives rise to the GA1-like pattern of DC5 metabolites in urine, tissues, and blood. Glutaric acid released from peroxisomes during DC11 chain-shortening can enter mitochondria for reactivation by the enzyme succinyl-CoA:glutarate-CoA transferase (SUGCT) and become substrate for glutaryl-CoA dehydrogenase (GCDH), the enzyme that is deficient in GA1. Our data provide proof-of-concept that the generation of dicarboxylic acids by ω-oxidation, which is stimulated during the same catabolic states known to trigger acute encephalopathy in GA1, may exacerbate disease by increasing the glutaryl-CoA substrate load in mitochondria.
(© 2025 Federation of American Societies for Experimental Biology.)
Σχόλια: Update of: bioRxiv. 2025 Feb 16:2025.02.13.637994. doi: 10.1101/2025.02.13.637994.. (PMID: 39990440)
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Grant Information: T34 GM136493 United States GM NIGMS NIH HHS; OD028654 HHS | National Institutes of Health (NIH); HD112518 HHS | National Institutes of Health (NIH); DK120531 HHS | National Institutes of Health (NIH); R01 DK090242 United States DK NIDDK NIH HHS; R01 HD103602 United States HD NICHD NIH HHS; R01 HD118270 United States HD NICHD NIH HHS; R01 HD112518 United States HD NICHD NIH HHS; HD118270 HHS | National Institutes of Health (NIH); HD103602 HHS | National Institutes of Health (NIH); DK090242 HHS | National Institutes of Health (NIH)
Contributed Indexing: Keywords: dicarboxylic acids; glutaric acidemia I; glutaryl‐coenzyme A; mitochondria; peroxisomes; succinyl‐coenzyme A
Substance Nomenclature: EC 1.3.8.6 (Glutaryl-CoA Dehydrogenase)
0 (Dicarboxylic Acids)
0 (Glutarates)
H849F7N00B (glutaric acid)
SCR Disease Name: Glutaric Acidemia I
Entry Date(s): Date Created: 20251106 Date Completed: 20251106 Latest Revision: 20260916
Update Code: 20260916
PubMed Central ID: PMC13066932
DOI: 10.1096/fj.202502381R
PMID: 41196119
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1530-6860
DOI:10.1096/fj.202502381R