Abstract 19228: Lack of Uncoupling Protein 2 (UCP2) Reduces Mitochondrial Calcium Uptake from the Endoplasmic Reticulum (ER), Triggering Mitochondrial Suppression and Pulmonary Hypertension (PHT)
Bibliographic record
Abstract
A metabolic shift from glucose oxidation to glycolysis due to suppressed mitochondrial function contributes to the hyperproliferation and resistance to apoptosis in resistance pulmonary arteries (PA) in PHT. Disruption of the ER-mitochondria unit, which can result from many PHT-triggers including hypoxia, prevents the transfer of ER Ca2+ to mitochondria, reducing the activity of Ca2+-sensitive mitochondrial enzymes and causing mitochondrial suppression. Emerging links between PHT and insulin resistance suggest a global metabolic dysfunction. The mitochondrial protein UCP2 is implicated in the uptake of ER-derived Ca2+ and loss-of-function UCP2 polymorphisms are associated with insulin resistance/obesity. We hypothesized that reduced UCP2-mediated mitochondrial Ca2+ uptake suppresses mitochondrial function and causes PHT. UCP2 is expressed in PA smooth muscle cells (PASMCs) from wild-type (WT), but not knockout (KO) mice. KO-PASMCs had lower mitochondrial Ca2+ levels than WT-PASMCs, at baseline and during histamine-stimulated ER Ca2+ release (FRET-imaging), despite intact ER-mitochondrial morphology (electron microscopy). In keeping with reduced mitochondrial Ca2+, KO-PASMCs had mitochondrial hyperpolarization, lower activity of Ca2+-sensitive mitochondrial enzymes, reduced mitochondrial reactive oxygen species and resistance to apoptosis. UCP2 KO-mice (which have an apparently normal phenotype) had a modest, but significant elevation in mean PA pressure (catheterization; 26±2 vs. 19±1 mmHg), total pulmonary resistance (1.37±.14 vs. 0.89±0.07 mmHg ml-1 min), %medial thickness, PASMC proliferation (% Ki67-positive), and resistance PA muscularization (n=6, p<0.05 for all). Chronic Hypoxia increased PA pressure in WT-mice to the level of the normoxic UCP2 KO-mice. However the UCP2 KO-mice were resistant to further exacerbation of PHT in vivo or hypoxia-induced PASMC changes in vitro. Since in hypoxia-induced PHT the ER-mitochondria unit is disrupted, the loss of UCP2 does not have additional effects. We conclude that lack of UCP2 causes mitochondrial suppression in PASMC and predisposes to PHT. UCP2 polymorphisms may predispose to PHT and potentially underlie the unexplained systemic metabolic abnormalities in PHT.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.008 | 0.002 |
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".