Abstract 382: Reduced Mitochondrial Function and Metabolic Dysregulation in Aneurysmal Fibulin-4 Mice.
Bibliographic record
Abstract
Thoracic aortic aneurysms are a life-threatening condition often diagnosed too late. The underlying mechanism is largely unknown. An accurate and early predictive biomarker for aneurysm formation has not yet been identified, although some molecular processes, such as disturbed TGF-β signalling, have been implicated. To discover novel robust biomarkers, we aimed to better understand the molecular mechanisms involved in aneurysm initiation and progression. In Fibulin-4 R/R mice, the extracellular matrix protein Fibulin-4 is 4-fold reduced, resulting in progressive ascending aneurysm formation and early death around 3 months of age. We performed LC-MS/MS proteomics and transcriptomics analyses on the aortas of Fibulin-4 R/R and Fibulin-4 +/+ mice. Protein and gene data sets were separately analysed for genotype specific differences with Ingenuity Pathway analysis tools. Intriguingly, we observed alterations in mitochondrial composition in aortas from Fibulin-4 R/R mice. Consistently, functional studies in Fibulin-4 R/R vascular smooth muscle cells (VSMCs) revealed lower oxygen consumption rates, but increased acidification rates compared to Fibulin-4 +/+ . The mitochondria in VSMCs of Fibulin-4 R/R mice were reduced in size and had increased complex I-IV levels. Furthermore, aortas of aneurysmal Fibulin-4 R/R mice displayed increased levels of ROS. Consistent with these findings, gene expression analyses revealed the dysregulation of metabolic pathways. In accordance, ketone levels in the blood of Fibulin-4 R/R mice were reduced and liver fatty acids were decreased, while liver glycogen was increased. As predicted by these findings, activity of PGC1α, a key regulator between mitochondrial function and organismal metabolism, was downregulated in Fibulin-4 R/R VSMCs. In conclusion, our data indicate altered mitochondrial function and metabolic dysregulation, leading to increased ROS levels and altered energy production, as a novel mechanism, which may contribute to thoracic aortic aneurysm formation. This discovery will not only provide new biomarkers that can be validated in human aortas, but they will also provide the rational for new interventions such as alterations in diet to prevent aneurysm formation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".