Integrating simulated and experimental data to identify mitochondrial bioenergetic defects in Parkinson’s Disease models
Bibliographic record
Abstract
Abstract Mitochondrial bioenergetics are vital for ATP production and are associated with several diseases, including Parkinson’s Disease. Here, we simulated a computational model of mitochondrial ATP production to interrogate mitochondrial bioenergetics under physiological and pathophysiological conditions, and provide a data resource that can be used to interpret mitochondrial bioenergetics experiments. We first characterised the impact of several common respiratory chain impairments on experimentally-observable bioenergetic parameters. We then established an analysis pipeline to integrate simulations with experimental data and predict the molecular defects underlying experimental bioenergetic phenotypes. We applied the pipeline to data from Parkinson’s Disease models. We verified that the impaired bioenergetic profile previously measured in Parkin knockout neurons can be explained by increased mitochondrial uncoupling. We then generated primary cortical neurons from a Pink1 KO mouse model of Parkinson’s, and measured reduced OCR capacity and increased resistance to Complex III inhibition. Here, our pipeline predicted that multiple respiratory chain impairments are required to explain this bioenergetic phenotype. Finally, we provide all simulated data as a user-friendly resource that can be used to interpret mitochondrial bioenergetics experiments, predict underlying molecular defects, and inform experimental design. Highlights The complexity of mitochondrial bioenergetics can make experimental data difficult to interpret. We simulated a computational model of mitochondrial bioenergetics in healthy and pathological conditions, and established an analysis pipeline to integrate model simulations with experimental data. We applied the pipeline to data from Parkinson’s Disease models to predict the molecular defects underlying Parkinson’s-related pathology. We provide all outputs in a user-friendly Excel file, which serves as a valuable resource to the community for insight into the effects of pathology on mitochondrial bioenergetics and for interpretation of experimental results.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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 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".