The role of transmembrane proton transport rates in mild mitochondrial uncoupling by arylamide substituted fatty acids
Bibliographic record
Abstract
Mitochondrial uncoupling by small molecule protonophores is a promising therapeutic strategy for leading diseases including obesity, diabetes and cancer, however the clinical potential of these agents is complicated by their associated toxicity. Protonophores that exclusively produce mild uncoupling can circumvent toxicity concerns, but these compounds or a framework to guide their design is currently lacking. In this study, we prepared a series of atypical arylamide-substituted fatty acid protonophores and found that specific aromatic substitution patterns can fine-tune their uncoupling activity. Notably, 3,4-disubstituted arylamides were found to increase cellular respiration and partially depolarise mitochondria without compromising ATP production or cell viability. These are hallmarks of mild uncoupling. In contrast, 3,5-disubstituted arylamides mimicked the full uncoupling effects of the classical uncouplers DNP and CCCP. Mechanistic studies revealed a diminished capacity for the 3,4-disubstituted arylamides to self-assemble into membrane permeable dimers in the rate limiting step of the protonophoric cycle. This translated into overall slower rates of transmembrane proton transport, and may account for their mild uncoupling activity. This work represents the first exploration of how proton transport rates influence mitochondrial uncoupling and provides a new conceptual framework for the rational design of mild uncouplers.
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How this classification was reachedexpand
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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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 teacher head, 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".