Abstract 12526: Snf1-related Kinase Improves Cardiac Mitochondrial Efficiency by Decreasing Mitochondrial Uncoupling
Bibliographic record
Abstract
Introduction: Ischemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in cardiac tissue death. Snf1-related Kinase (SNRK) is a serine/threonine kinase with sequence similarity to AMP-activated protein kinase, but its function is unknown. We found that SNRK is increased in hearts from patients with ischemic cardiomyopathy, and our gene array data suggested that SNRK alters metabolic genes. Here, we assessed the hypothesis that SNRK improves cardiac metabolic efficiency and mitochondrial uncoupling, and protects against ischemia/reperfusion (I/R) injury. Results: Cardiac-specific SNRK transgenic (TG) mice displayed decreased glycolysis, glucose oxidation, and palmitate oxidation compared to wild type littermate controls in perfused working hearts. However, cardiac power, contractility, ATP, and triglyceride and glycogen stores were maintained, while oxygen consumption was reduced, demonstrating that SNRK TG mice have increased cardiac metabolic efficiency. Consistent with improved cardiac metabolic efficiency, SNRK TG mice exhibited decreased infarct size after I/R. Mitochondria from SNRK TG mice also had reduced respiration, and increased respiratory control ratio and mitochondrial membrane potential, indicating reduced mitochondrial uncoupling. Uncoupling protein 3 (UCP3) levels were also decreased. Conversely, hearts from heterozygous SNRK knockout mice had increased glucose and palmitate oxidation and UCP3. SNRK knockdown in cardiac cells decreased mitochondrial efficiency, which was abolished with UCP3 knockdown. To determine the mechanism for the regulation of UCP3 by SNRK, we performed yeast two-hybrid assay, and identified tribbles homolog 3 (Trib3) to bind to SNRK. Furthermore, Trib3 enabled downregulation of UCP3 by downregulating the expression of PPARα. Conclusions: Our results demonstrate that overexpression of SNRK decreases cardiac metabolic substrate usage and oxygen consumption but maintains cardiac function and enhanced mitochondrial coupling. We also identify a binding partner of SNRK, Trib3, which is upregulated by SNRK in mice and mediates the regulation of PPARα and UCP3 by SNRK.
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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 | 0.000 |
| 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) | 0.007 | 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".