Abstract 4141043: Upregulation of Dynamin 2 (DNM2) Increases Mitochondrial Fission and Cell Proliferation in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Introduction: Mitochondrial fission is mediated by dynamin related protein-1 (Drp1) activation; however, to complete fission, we have evidence that Drp1 requires assistance from the GTPase dynamin 2 (DNM2). Hypothesis: DNM2 interacts with Drp1 to regulate mitotic fission and cell cycle progression, permitting the hyperproliferative phenotype of pulmonary artery smooth muscle cells (PASMC) in pulmonary arterial hypertension (PAH). Methods: Colocalization of Drp1 and DNM2 was assessed using STED super resolution confocal microscopy. Interaction of Drp1 and DNM2 was confirmed by immunoprecipitation. The role of DNM2’s GTPase domain in mitochondrial targeting was assessed by heterologous expression of truncated constructs. Changes in transcriptomic signature from silencing DNM2 in PAH human PASMC (hPASMC) were measured by RNA-seq. DNM2 expression in control vs PAH was quantified in hPASMC (n=4-5/group) and lungs from human (n=5/group), monocrotaline (MCT) (n=4-5/group) and SU5416/hypoxia (Su/Hx) (n=4-5/group) induced rodents using immunoblots, immunohistochemistry and immunofluorescence. DNM2’s effects on cell proliferation, cell cycle and apoptosis were assessed by flow cytometry. siDNM2 was nebulized to rats with established MCT-PAH. Results: DNM2 is significantly increased in human and rodent PAH and silencing DNM2 reduces mitochondrial fission and cell proliferation and induces apoptosis and cell cycle blockade in the G0/G1 phase in PAH PASMC. DNM2 and Drp1 interact at mitochondrial fission sites. DNM2’s translocation to the mitochondria is Drp-dependent and requires DNM2’s GTPase domain. Silencing DNM2 downregulates the Regulator of Cell Cycle, RGCC . Augmenting DNM2 in normal PASMC induces mitochondrial fission and cell proliferation. miR-124-3p, which negatively regulates DNM2, is decreased in PAH PASMC. Augmenting miR-124-3p decreases DNM2 expression, inhibits fission and proliferation and induces apoptosis in PAH PASMC. Silencing STAT3 (also negatively regulated by miR-124-3p) reduces DNM2 and inhibits fission. siDNM2 regresses PAH in MCT-PAH rats. Conclusion: DNM2 binds to Drp1 and translocates to mitochondria, regulating fission. A pathological increase in DNM2 expression, driven by decreased miR-124a-3p and STAT3 activation, increases mitochondrial fission, proliferation and inhibits apoptosis in PAH PASMC. DNM2 regulates cell proliferation via RGCC. DNM2 is a fission mediator and its regulatory pathway offers potential PAH therapeutic targets.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".