The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1
Bibliographic record
Abstract
Defects in mitochondrial translation are associated with a remarkable, but unexplained diversity of clinical phenotypes. Here we have investigated the molecular basis for tissue specificity in patients with a fatal hepatopathy due to mutations in the mitochondrial translation elongation factor EFG1. Blue-native gel electrophoresis revealed unique, tissue-specific patterns in the nature and severity of the defect. Liver was the most severely affected tissue, with less than 10% residual assembly of complexes I and IV, and a 50% decrease in complex V. Skeletal muscle showed a 50% reduction in complex I, and complexes IV and V were 20% of control. In fibroblasts, complexes I and IV were 20% of control, and there was a 40-60% reduction in complexes III and V. In contrast, except for a 50% decrease in complex IV, all complexes were near normal in heart. The severity of the defect paralleled the steady-state level of the mutant EFG1 protein, which varied from 60% of control in heart to undetectable in liver. The ratio of translation elongation factors EFTu:EFTs increased from 1:6 to 1:2 in patient heart, whereas in liver it decreased from 1:1 to 1:4. Over-expression of either EFTu or EFTs in control and patient fibroblasts produced dominant negative effects, indicating that the relative abundance of these factors is an important determinant of translation efficiency. Our results demonstrate marked differences among tissues in the organization of the mitochondrial translation system and its response to dysfunction, and explain the severe hepatopathy, but normal cardiac function in EFG1 patients.
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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".