Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of <i>RRM2B</i> mtDNA depletion syndrome
Bibliographic record
Abstract
Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are rare, clinically heterogeneous mitochondrial disorders resulting from nuclear variants in genes of the mitochondrial DNA replication or maintenance machinery. Supplementation with pyrimidine deoxynucleosides have been beneficial in patients and mice with TK2-related MDDS, however, it has not been systematically explored in other forms of MDDS. To investigate the effect of deoxynucleoside supplementation in mitigating the disease in mitochondrial DNA depletion due to pathogenic RRM2B variants, we generated a novel zebrafish knock-out model of this disease and studied the effect of different combinations of deoxynucleosides. Zebrafish larvae carrying a homozygous nonsense mutation in rrm2b present with impaired movement, reduced mtDNA copy number and elevated lactate. Supplementation with different combination of deoxynucleosides was performed, resulting in increased mtDNA copy numbers when supplemented with the two purine deoxynucleosides (dGuo and dAdo), while other combinations had no effect or even further compromised mtDNA copy number in zebrafish. In parallel with increased mtDNA copy number, we detected improved movement and reduction of lactate in the rrm2b-/- fish, confirming the beneficial effect of deoxynucleosides on the whole organism. This treatment did not result in any deleterious effect in wild type and heterozygous fish. Our data suggest that supplementation with deoxynucleosides may be beneficial and should be further investigated in RRM2B-related disease, adding to the growing evidence that it is a valid therapeutic approach which can be trialled for treating a wider range of genetic forms of MDDS.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 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".