Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mt-ISR
Bibliographic record
Abstract
Abstract Mutations in CHCHD10 and CHCHD2 , coding for two paralogous mitochondrial proteins, have been identified in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), and Parkinson’s disease (PD). Here we investigated the biological roles of these proteins during vertebrate development using knockout (KO) models in zebrafish. We demonstrate that loss of either or both proteins leads to a motor impairment, reduced survival, and compromised neuromuscular junction (NMJ) integrity in larval zebrafish. Compensation by Chchd10 was observed in the chchd2 -/- model, but not by Chchd2 in the chchd10 -/- model. The assembly of mitochondrial respiratory chain Complex I was impaired in chchd10 -/- and chchd2 -/- zebrafish larvae, but unexpectedly not in the double chchd10 -/- & chchd2 -/- model, suggesting that reduced mitochondrial Complex I cannot be solely responsible for the observed phenotypes, which are generally more severe in the double KO. Activation of the mitochondrial integrated stress response (mt-ISR) was only observed in the double KO model, possibly implicating this pathway in the recovery of the Complex I defect, and suggesting that Complex I assembly defect in our single KO is independent of the mt-ISR. Our results demonstrate that both proteins are required for normal vertebrate development, but their precise molecular function in the mitochondrial biology of motor neurons remains to be discovered.
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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 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".