Abstract 15702: Role of the Drp-1 Receptors Mid49 and Mid51 in Regulating Fission and Cell Proliferation in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction that is partially due to hyperproliferation of apoptosis-resistant pulmonary arterial smooth muscle cells (PASMCs). This “neoplastic phenotype” of PAH PASMCs is due, in part, to excessive mitochondrial fission caused by activation of dynamin related protein-1 (Drp-1). A pool of Drp-1 exists in the cytosol. Upon activation it is recruited to the mitochondrial outer membrane by Drp-1 receptor proteins, such as MiD49 and MiD51. The biological functions of these newly discovered Drp-1 receptors in diseases, including PAH, is poorly understood. We hypothesize that in PAH increased expression of MiD49 and MiD51 contribute to increased mitochondrial fission and excessive cell proliferation. Methods: Immunoblots quantified MiD49 and MiD51 expression in human control (n=3) and PAH PASMCs (n=6). The effects of silencing expression of MiD49 and MiD51, using small interfering RNA (siRNA), on cell proliferation, cell cycle progression, and rates of apoptosis were assessed using flow cytometry, and a cell death ELISA assay, respectively. Mitochondrial network structure was assessed using confocal imaging of cells stained with tetramethylrhodamine (TMRM). Results: MiD49 and MiD51 expression was increased in human PAH PASMCs vs control PASMCs (P<0.05). There was marked inter-individual variation in expression profile with some patients expressing excess MiD49 and others excess MiD51. PAH PASMCs had fragmented mitochondrial networks and both siMiD49 and siMiD51 increased mitochondrial fusion. Either siMiD49 or siMiD51 completely blocked the proliferation of PAH PASMCs by arresting the cells in the G1/G0 phase. In contrast, only siMiD51 induced apoptosis in PAH PASMCs. Conclusion: MiD49 and MiD51 are critically involved in mitochondrial fission and cell proliferation in human PAH PASMCs. Inhibition of MiD49 or MiD51 enhances mitochondrial fusion and reduces cell proliferation, while silencing MiD51 also induces apoptosis. These newly discovered Drp-1 binding partners are promising therapeutic targets 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) | 0.005 | 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".