NDUFS2 (NADH:Ubiquinone oxidoreductase core subunit S2) in Mitochondrial Electron Transport Chain Complex I is Critical to Oxygen Responsiveness of Human Ductus Arteriosus Smooth Muscle Cells
Bibliographic record
Abstract
Abstract Rationale Mitochondria in ductus arteriosus (DA) smooth muscle cells (DASMC) are oxygen sensors that trigger O 2 -induced vasoconstriction at birth; however, the molecular mechanisms of mitochondrial oxygen sensing are not fully understood. Many redox sensor proteins are conserved in the mammalian adult homeostatic oxygen sensing system, including NDUFS2 (NADH:Ubiquinone oxidoreductase core subunit S2), a component of mitochondrial Complex I that contributes to oxygen sensing in adult pulmonary arteries. Here we compared the role of NDUFS2 in DA oxygen sensing, to that of other Complex I subunits and putative O 2 -sensor subunits, including: NADH:Ubiquinone oxidoreductase core subunit S1 (NDUFS1), NADH:Ubiquionone oxidoreductase core subunit S7 (NDUFS7), Ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1 (UQCRFS1), and Cytochrome c oxidase subunit 4I2 (COX4I2). Methods Human DASMC were grown in hypoxia (2.5% O 2 , pO 2 =41mmHg). Oxygen responsiveness of DASMC was assessed, measuring O 2 -induced changes in intracellular calcium, [Ca 2+ ] i , cell length, and mitochondrial reactive oxygen species (mROS) production. DASMC were treated for 48-hours with silencing RNA (siRNA) targeting NDUFS2, NDUFS1, NDUFS7, UQCRFS1, or COX4I2; knockdown was confirmed using qPCR and immunoblot. Mitochondrial metabolic consequences were assessed with micropolarimetry and Complex I, III, and IV activity assays. 3’RNA sequencing was used to explore the impact of gene knockdown on the DASMC molecular signature. Results The O 2 -induced increase in [Ca 2+ ] i in siControl-treated cells (+18.6±2.3%) was reduced by siNDUFS2 (+5.5±1.5%, p<0.0001), but unchanged by other siRNAs. siNDUFS2 also uniquely depressed O 2 -induced DASMC shortening (from -18.4±1.1% to -8.9±0.77%, p<0.0001), and mROS generation (+24±4.9% untreated versus -6.6±5.4% siNDUFS2, p<0.0001). The mitochondrial antioxidant MitoTEMPO also inhibited mROS (+2.9±4.5%, p=0.001) and attenuated oxygen-induced cell shortening (8.43±0.91%, p=0.0003). Knockdown of NDUFS2 and other ETC subunits did not inhibit mitochondrial respiration or ETC activity. Transcriptomics revealed unique changes in mitochondrial pathways with siNDUFS2. Conclusions NDUFS2 regulates mROS and acts as a mitochondrial oxygen sensor in human DASMC.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".