Early complex I assembly defects result in rapid turnover of the ND1 subunit
Bibliographic record
Abstract
Complex I (CI, NADH ubiquinone oxidoreductase), the largest complex of the respiratory chain, is composed of 45 structural subunits, 7 of which are encoded in mtDNA. At least 10 factors necessary for holoenzyme assembly have been identified; however, the specific roles of most of them are not well understood. We investigated the role of NDUFAF3, NDUFAF4, C8orf38 and C20orf7, four early assembly factors, in the translation of the mtDNA-encoded CI structural subunits. Transient, or stable, siRNA-mediated knock-down of any of these factors abrogated the assembly of CI, and resulted in a specific decrease in the labeling of the ND1 subunit in a pulse translation experiment, whereas knock-down of NDUFAF2, a late assembly factor, did not affect ND1 translation. Pulse-chase experiments in cells knocked down for NDUFAF3 showed that the half-life of ND1 in the chase was reduced 4-fold, fully accounting for the decrease in pulse labeling. Transient, short-term knock-down of the m-AAA protease AGF3L2 in cells that had been depleted of any of the early CI assembly factors completely rescued the ND1 labeling phenotype, confirming that it is not a synthesis defect, but rather results from rapid proteolysis of newly synthesized ND1. NDUFAF3 co-immunoprecipitated with NDUFAF4, and three matrix arm structural subunits (NDUFS2, NDUFA9, NDUFS3) that are found in a 400 kDa assembly intermediate containing ND1. These data suggest that the four early CI assembly factors have non-redundant functions in the assembly of a module that docks and stabilizes newly synthesized ND1, nucleating assembly of the holoenzyme.
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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".