Loss of CHCHD10–CHCHD2 complexes required for respiration underlies the pathogenicity of a CHCHD10 mutation in ALS
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Bibliographic record
Abstract
Coiled-helix coiled-helix domain containing protein 10 (CHCHD10) and its paralogue CHCHD2 belong to a family of twin CX9C motif proteins, most of which localize to the intermembrane space of mitochondria. Dominant mutations in CHCHD10 cause amyotrophic lateral sclerosis (ALS)/frontotemporal dementia, and mutations in CHCHD2 have been associated with Parkinson's disease, but the function of these proteins remains unknown. Here we show that the p.R15L CHCHD10 variant in ALS patient fibroblasts destabilizes the protein, leading to a defect in the assembly of Complex I, impaired cellular respiration, mitochondrial hyperfusion, an increase in the steady-state level of CHCHD2, and a severe proliferation defect on galactose, a substrate that forces cells to synthesize virtually all of their ATP aerobically. CHCHD10 and CHCHD2 appeared together in distinct foci by immunofluorescence analysis and could be quantitatively immunoprecipitated with antibodies against either protein. Blue native polyacrylamide gel electrophoresis analyses showed that both proteins migrated in a high molecular weight complex (220 kDa) in control cells, which was, however, absent in patient cells. CHCHD10 and CHCHD2 levels increased markedly in control cells in galactose medium, a response that was dampened in patient cells, and a new complex (40 kDa) appeared in both control and patient cells cultured in galactose. Re-entry of patient cells into the cell cycle, which occurred after prolonged culture in galactose, was associated with a marked increase in Complex I, and restoration of the oxygen consumption defect. Our results indicate that CHCHD10-CHCHD2 complexes are necessary for efficient mitochondrial respiration, and support a role for mitochondrial dysfunction in some patients with ALS.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 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 it