Cobalamin‐deficiency results in altered partitioning of mitochondrial one‐carbon units to formate
Bibliographic record
Abstract
Vitamin B 12 , a co‐factor for methionine synthase, plays an important role in folate‐dependent remethylation of homocysteine. We have shown that cobalamin deficiency results in a marked elevation in plasma formate. De novo production of formate in rats was determined as described by Morrow et al (JBC 2015). Formate production from one‐carbon precursors by isolated rat liver mitochondria was measured by GC‐MS. 14 CO 2 production from 3‐[ 14 C]‐serine by isolated rat liver mitochondria, expression of key genes (RT‐qPCR) and changes in protein expression (immunoblot) were also determined. Vitamin B 12 ‐deficient rats (B 12 ‐def) showed a 55% increase in endogenous formate production, consistent with the elevated formate levels. Formate production by isolated mitochondria from serine, dimethylglycine, and sarcosine was increased by at least 60% in B 12 ‐def animals while 14 CO 2 production from serine by these mitochondria was 26% lower compared to replete controls. The expression of Mthfd1l in B 12 ‐def animals was unchanged but the expression of Aldh1l1 and Aldh1l2 was reduced by 40–60% of that in the livers of control animals. We suggest that the partitioning of mitochondrial formyl‐THF between oxidation to CO 2 (by ALDH1L2) and production of free formate (by MTHFD1L) is a key control point in one‐carbon metabolism. In B 12 ‐def the decreased flux through ALDH1L2, in the face of a constant rate of 10‐formyl‐THF disposition can explain the increased production and increased concentration of formate. We speculate that the decreased hepatic SAM levels found in B 12 ‐def animals may cause increased production of one‐carbon groups in the form of formate to replenish hepatic SAM. Since mitochondrial formate becomes available to the cytosol we suggest that this metabolic bifurcation may regulate the entry of formate into the cytosolic one‐carbon pool. Support or Funding Information Supported by CIHR, RDC, and Memorial University of Newfoundland
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".