Λεπτομέρειες βιβλιογραφικής εγγραφής
| Τίτλος: |
Odd-chain dicarboxylic acid feeding recapitulates the biochemical phenotype of glutaric aciduria type 1 in mice. |
| Συγγραφείς: |
Richert AC, Zhang Y, Bharathi SS, Hernandez A, Dodatko T, Bons J, Stauffer B, Yu C, Schilling B, Houten SM, Goetzman ES |
| Πηγή: |
BioRxiv : the preprint server for biology [bioRxiv] 2025 Feb 16. Date of Electronic Publication: 2025 Feb 16. |
| Τύπος έκδοσης: |
Journal Article; Preprint |
| Γλώσσα: |
English |
| Στοιχεία περιοδικού: |
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| 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, DC 11 ) recreates the biochemical phenotype of GA1. Odd-chain dicarboxylic acids like DC 11 are not present in food but can arise from several endogenous processes, such as lipid peroxidation and fatty acid ω-oxidation. DC 11 is chain-shortened in peroxisomes to glutaryl (DC 5 )-CoA, which then gives rise to the GA1-like pattern of DC 5 metabolites in urine, tissues, and blood. Glutaric acid released from peroxisomes during DC 11 chain-shortening can enter mitochondria, be activated to CoA by the enzyme succinyl-CoA:glutarate-CoA transferase (SUGCT), and become substrate for glutaryl-CoA dehydrogenase (GCDH), the enzyme that is mutated 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. |
| Σχόλια: |
Update in: FASEB J. 2025 Nov 15;39(21):e71215. doi: 10.1096/fj.202502381R.. (PMID: 41196119) |
| Grant Information: |
R01 HD112518 United States HD NICHD NIH HHS; S10 OD028654 United States OD NIH HHS |
| Entry Date(s): |
Date Created: 20250224 Date Completed: 20251112 Latest Revision: 20251112 |
| Update Code: |
20260130 |
| PubMed Central ID: |
PMC11844465 |
| DOI: |
10.1101/2025.02.13.637994 |
| PMID: |
39990440 |
| Βάση Δεδομένων: |
MEDLINE |