Reduced methionine synthase ( Mtr ) expression creates a functional vitamin B12 deficiency that leads to uracil accumulation in mouse mitochondrial DNA
Rattachement africain : us. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Abstract Adequate thymidylate (dTMP or the “T” base in DNA) levels are essential for stability of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Folate and vitamin B12 (B12) are essential cofactors in folate-mediated one carbon metabolism (FOCM), a metabolic network which supports synthesis of nucleotides (including dTMP) and methionine. Perturbations in FOCM impair dTMP synthesis, causing misincorporation of uracil (or a “U” base) into DNA. During B12 deficiency, cellular folate accumulates as 5-methyltetrahdryfolate (5-methyl-THF), limiting nucleotide synthesis. The purpose of this study was to determine how B12 deficiency and dietary folate interact to affect mtDNA integrity and mitochondrial function in mouse liver. Mice expressing reduced methionine synthase ( Mtr ) levels were used to create a functional B12 deficiency. Folate accumulation, uracil levels, mtDNA content, and oxidative phosphorylation capacity were measured in male Mtr +/+ and Mtr +/- mice weaned onto either a folate-sufficient control diet (2 mg/kg folic acid, C) or a folate-deficient diet (FD, lacking folic acid) for 7 weeks. Mtr heterozygosity led to increased liver 5-methyl-THF levels. Mtr +/- mice consuming the C diet also exhibited a 40-fold increase in uracil in liver mtDNA. However, the combination of Mtr heterozygosity and exposure to the FD diet partially alleviated the level of uracil accumulation in mtDNA. Furthermore, Mtr +/- mice exhibited a 25% decrease in liver mtDNA content and a 20% decrease in maximal oxygen consumption rates. Impairments in mitochondrial FOCM are known to lead to increased uracil in mtDNA. This study demonstrates that impaired cytosolic dTMP synthesis also leads to increased uracil in mtDNA.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Reduced methionine synthase ( <i>Mtr</i> ) expression creates a functional vitamin B12 deficiency that leads to uracil accumulation in mouse mitochondrial DNA
- Date Crossref
- 29/08/2022
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
Cornell University Division of Nutritional Sciences pays non établi dans la noticeUniversité ou école supérieure
-
La Jolla Bioengineering Institute pays non établi dans la noticeOrganisation à but non lucratif
-
University of Colorado Anschutz Department of Medicine pays non établi dans la noticeUniversité ou école supérieure
-
University of Colorado Denver pays non établi dans la noticeUniversité ou école supérieure
-
University of California Department of Bioengineering pays non établi dans la noticeUniversité ou école supérieure
-
Salk Institute for Biological Studies pays non établi dans la noticeOrganisation à but non lucratif
-
Molecular and Cell Biology Laboratory pays non établi dans la noticeStructure de recherche
Division of Nutritional Sciences — Cornell University, La Jolla Bioengineering Institute et Department of Medicine — University of Colorado Anschutz, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.