Mitochondrial complex I mutations in Caenorhabditis elegans produce cytochrome c oxidase deficiency, oxidative stress and vitamin-responsive lactic acidosis
Bibliographic record
Abstract
Mitochondrial dysfunction, with an estimated incidence of 1 in 10 000 live births, is among the most common genetically determined conditions. Missense mutations in the human NDUFV1 gene, which encodes the 51 kDa active site subunit of the NADH-ubiquinone oxidoreductase or complex I, can lead to severe neurological disorders. Owing to the rare and often sporadic nature of mitochondrial disorders, the mechanisms of pathogenesis of most mutations remain poorly understood. We have generated transgenic strains of Caenorhabditis elegans that express disease-causing mutations in the nuo-1 gene, the C. elegans homolog of the NDUFV1 gene. The transgenic strains demonstrate hallmark features of complex I dysfunction such as lactic acidosis and decreased NADH-dependent mitochondrial respiration. They are also hypersensitive to exogenous oxidative stress, suggesting that cellular defense mechanisms against reactive oxygen species are already taxed by an endogenous stress. The lactic acidosis induced by the NDUFV1 mutations could be partially corrected with the vitamins riboflavin and thiamine or with sodium dichloroacetate, an activator of the pyruvate dehydrogenase complex, resulting in significant increases in animal fitness. Surprisingly, cytochrome c oxidase activity and protein levels were reduced, establishing a connection between complexes I and IV. Our results indicate that complex I mutations exert their pathogenic effects in multiple ways: by impeding the metabolism of NADH, by increasing the production of reactive oxygen species, and by interfering with the function or assembly of other mitochondrial respiratory chain components.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".