Lethal Arg9Cys phospholamban mutation increases the mitochondrial fission protein (Drp‐1) activity
Bibliographic record
Abstract
An Arg 9 to Cys point mutation in phospholamban (PLN) is the leading cause of dilated cardiomyopathy (DCM) in both humans and in transgenic mice (TgPLN R9C mice). An earlier proteomics analysis of these mice showed that many proteins classified under the Gene Ontology (GO) term functional categories of ‘reduced mitochondrial function' and ' disruption of energy production' were significantly reduced. Here, we show that COX activity measured in mitochondria isolated from ventricles of these mice was significantly reduced compared to wild type. At the same time, electron microscopy showed extensive mitochondrial damage. Since PLN is a regulator of the sarco/endo plasmic reticulum Ca 2+ ‐ATPase (SERCA2a), we examined the translocation of stromal interaction molecule 1 (STIM1) to speculate Ca 2+ store in SR. STIM1 formed punctae in R9C cells, indicating a reduction in the size of the Ca 2+ store. This change in the Ca 2+ store was associated with ER stress and changes in the phosphorylation status of several proteins; in particular, phosphorylation of the mitochondrial fission protein 1 (Drp1) was decreased. Immunoblotting and immunofluorescence in whole cells showed enhanced dephosphorylation of Drp1, increased cytochrome c release and enhanced cleavage of caspase‐3, associated with mitochondrial damage in 8‐week old TgPLN R9C mouse hearts. We propose that the dephosphorylation and activation of Drp1, leading to enhanced mitochondrial fission, may play an early role in the progression to DCM, triggered by Ca 2+ dysregulation in TgPLN R9C mice.
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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) | 0.001 | 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) | 0.003 | 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".