The role of transmembrane proton transport rate in mild mitochondrial uncoupling produced by arylamide substituted fatty acids.
Bibliographic record
Abstract
Mitochondrial uncoupling by small molecule protonophores is a promising therapeutic strategy for treatment of cancer and other diseases, however the toxicity associated with uncoupling is a major challenge. A possible solution is the development of mild uncouplers that partially depolarise mitochondria without affecting ATP production. In this study, we prepared a series arylamide substituted fatty acid protonophores and demonstrate that arylamides with appropriate aromatic substitution patterns produce mild uncoupling. Specifically, 3,4-substituted arylamides increased respiration in MDA-MB-231 breast cancer cells and partially collapsed mitochondrial proton gradients without affecting ATP production or cell viability. In contrast, the actions of 3,5-substituted arylamides were similar to those of known full uncouplers DNP and CCCP and decreased intracellular ATP levels. Using a vesicle-based proton transport assay, we found that the rates of transmembrane proton transport by the 3,4-substituted arylamides were slower than those of their 3,5-substituted counterparts, which is attributed to a diminished capacity of 3,4-substituted arylamides to form membrane permeable dimers in the rate limiting step of the protonophoric cycle. This is the first study to assess the role of proton transport rate in protonophore-mediated mitochondrial uncoupling, and the results indicate that development of protonophores with limited proton transport rates may be a viable strategy towards identifying mild uncouplers.
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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) | 0.000 | 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 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".