Electron Leak From the Mitochondrial Electron Transport Chain Complex I at Site I <sub>Q</sub> Is Crucial for Oxygen Sensing in Rabbit and Human Ductus Arteriosus
Bibliographic record
Abstract
Background As partial pressure of oxygen (pO 2 ) rises with the first breath, the ductus arteriosus (DA) constricts, diverting blood flow to the pulmonary circulation. The DA's O 2 sensor resides within smooth muscle cells. The DA smooth muscle cells’ mitochondrial electron transport chain (ETC) produces reactive oxygen species (ROS) in proportion to oxygen tension, causing vasoconstriction by regulating redox‐sensitive ion channels and enzymes. To identify which ETC complex contributes most to DA O 2 sensing and determine whether ROS mediate O 2 sensing independent of metabolism, we used electron leak suppressors, S1QEL (suppressor of site I Q electron leak) and S3QEL (suppressor of site III Qo electron leak), which decrease ROS production by inhibiting electron leak from quinone sites I Q and III Qo , respectively. Methods and Results The effects of S1QEL, S3QEL, and ETC inhibitors (rotenone and antimycin A) on DA tone, mitochondrial metabolism, O 2 ‐induced changes in intracellular calcium, and ROS were studied in rabbit DA rings, and human and rabbit DA smooth muscle cells. S1QEL's effects on DA patency were assessed in rabbit kits, using micro computed tomography. In DA rings, S1QEL, but not S3QEL, reversed O 2 ‐induced constriction ( P =0.0034) without reducing phenylephrine‐induced constriction. S1QEL did not inhibit mitochondrial metabolism or ETC‐I activity. In human DA smooth muscle cells, S1QEL and rotenone inhibited O 2 ‐induced increases in intracellular calcium ( P =0.02 and 0.001, respectively), a surrogate for DA constriction. S1QEL inhibited O 2 ‐induced ROS generation ( P =0.02). In vivo, S1QEL prevented O 2 ‐induced DA closure ( P <0.0001). Conclusions S1QEL, but not S3QEL, inhibited O 2 ‐induced rises in ROS and DA constriction ex vivo and in vivo. DA O 2 sensing relies on pO 2 ‐dependent changes in electron leak at site I Q in ETC‐I, independent of metabolism. S1QEL offers a therapeutic means to maintain DA patency.
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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) | 0.001 | 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 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".