Author response: The Role of ATP Synthase Subunit e (ATP5I) in Mediating the Metabolic and Antiproliferative Effects of Biguanides
Bibliographic record
Abstract
Here we identify the subunit e of F1Fo-ATP synthase (ATP5I) as a target of medicinal biguanides. ATP5I maintains the stability of F1Fo-ATP synthase dimers which is crucial for shaping cristae morphology. Although its roles have been mainly studied in yeast models, its function in cellular energy metabolism within the context of cancer remains poorly characterized. In this study, we demonstrate that ATP5I interacts with a biguanide analogue in vitro and disabling its expression by CRISPR-Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide treated cells including a decrease in the levels of some respiratory complex subunits, mitochondrial morphology alterations, inhibition of oxidative phosphorylation (OXPHOS) and a compensatory increase in glycolysis. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and anti-proliferative effects of metformin and phenformin. These findings highlight ATP5I as a significant antineoplastic mitochondrial target of medicinal biguanides, opening new opportunities for the development of mitochondrial-targeted therapies.
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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 | 0.002 | 0.016 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.004 | 0.002 |
| Insufficient payload (model declined to judge) | 0.151 | 0.067 |
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".