Abstract 15168: The Role of Mitochondrial Fission Factor (MFF) and Increased Midzone Mitochondrial Fission in Pulmonary Arterial Hypertension: Implications for Proliferation, Mitophagy, and Apoptosis
Bibliographic record
Abstract
Introduction: The obstructive vasculopathy in pulmonary arterial hypertension (PAH) results from unrestricted proliferation and impaired apoptosis of pulmonary artery smooth muscle cells (PASMC). This pseudoneoplastic phenotype is partly due to increased mitotic fission i.e. the highly coordinated processes of mitochondrial fission and nuclear division. Two types of mitochondrial fission have been reported: peripheral fission, which eliminates damaged terminal portions of mitochondria via mitophagy, and midzone fission, which is linked to mitochondrial biogenesis and cellular proliferation. While all fission involves dynamin related protein 1 (Drp1), the Drp1 binding partner differs between these processes with mitochondrial fission factor (MFF) mediating midzone fission, whilst fission protein 1 (Fis1) governs peripheral fission. Here we explore the role of MFF and Fis1 in the pathogenesis of PAH. Hypothesis: Midzone fission is increased in PAH PASMC and inhibiting midzone fission by downregulating MFF will decrease cell proliferation and induce apoptosis. Methods: MitoMeter, a mitochondrial segmentation and tracking application, was adapted for automated analysis of the location of mitochondrial fission events. Immunoblots were used to assess the expression of MFF and Fis1 in control (n=4) vs. PAH (n=5) human PASMC. Flow cytometry was used to assess cell proliferation (EdU) and rates of apoptosis (Annexin V) (n=3). Results: Midzone fission, as a % of total fission events, is increased (PAH= 48.7%±6.9, Ctrl = 28.9%± 5.1p<0.05). Moreover, MFF expression is increased in PAH PASMC (p<0.05). Conversely, peripheral fission is decreased (PAH=51.2%±6.9, Ctrl = 71.0±5.1). Silencing MFF inhibited midzone fission (siCtrl=54.93.1%, siMFF = 39.37.4%), while Fis1 knockdown inhibited peripheral fission in PAH PASMC (siCtrl = 45.13.1%, siFis1 = 36.91.9%), p<0.05 each. Inhibiting MFF inhibited PAH PASMC proliferation (siCtrl =36.50.9%, siMFF = 23.50.5%, p<0.05) and induced apoptosis in PAH PASMC (siCtrl=3.90.3% versus siMFF 7.40.2%, p<0.05). Conclusion: MFF mediated midzone fission is upregulated in PAH PASMC contributing to increased proliferation, and reduced apoptosis. Inhibiting MFF may be a new therapeutic strategy in PAH.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 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".