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 Background Mitochondria in ductus arteriosus smooth muscle cells (DASMCs) are oxygen sensors triggering vasoconstriction at birth; however, the oxygen sensing mechanisms are incompletely understood. Given the conserved role of mitochondrial Complex I subunit NDUFS2 in other oxygen-sensing tissues, we examined its role in DASMC oxygen sensing, comparing it to other Complex I subunits (NDUFS1 and NDUFS7) and putative O 2 -sensor subunits (UQCRFS1 and COX4I2). Methods Human DASMCs were grown in hypoxia (pO 2 =41mmHg). Oxygen responsiveness was assessed, measuring changes in intracellular calcium, [Ca 2+ ] i , cell length, and mitochondrial reactive oxygen species (mROS). DASMCs were treated for 48-hours with control siRNA versus siRNA targeting NDUFS2, NDUFS1, NDUFS7, UQCRFS1, or COX4I2. qPCR and immunoblotting confirmed knockdown. 3’RNA sequencing assessed transcriptional changes following siRNA. Results Oxygen increased mitochondrial fission, [Ca 2+ ] i , and constricted DASMCs. 48-hours post-treatment, siNDUFS2 selectively depressed oxygen-induced increase in [Ca 2+ ] i (siControl +18.6±2.3%, siNDUFS2 +5.5±1.5%, p<0.0001), DASMC shortening (from 18.4±1.1% to 8.9±0.8%, p<0.0001), and mROS (+24±4.9% untreated, -6.6±5.4% post-siNDUFS2, p<0.0001), without altering the KCl response or depressing respiration. The mitochondrial antioxidant MitoTEMPO reduced mROS (2.9±4.5%, p=0.001) and attenuated oxygen-induced DASMC shortening (8.4±0.9%, p=0.0003). Transcriptomics revealed unique changes in mitochondrial pathways post siNDUFS2. Conclusions NDUFS2 regulates mROS and is a mitochondrial oxygen sensor in human DASMCs. Impact We demonstrated a unique role of Complex I subunit NDUFS2 (NADH:Ubiquinone Oxidoreductase Core Subunit S2), amongst putative oxygen-sensing electron transport chain subunits, in the responsiveness of human ductus arteriosus (DA) smooth muscle cells (DASMCs) to oxygen. NDUFS2 knockdown inhibited oxygen-induced DASMC constriction and generation of mitochondrial reactive oxygen species, at a timepoint prior to inhibition of mitochondrial respiration and without inhibition of KCl-induced constriction. While mitochondria are known DA oxygen sensors, this work identifies NDUFS2 as a molecular mediator of human DA oxygen sensing within the mitochondria, enhancing our understanding of a vital physiologic phenomenon and providing a novel potential therapeutic target to modulate ductal patency.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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".