Abstract 284: Loss of Cardiomyocyte General Control of Amino-Acid Synthesis 5-like 1 Expression Impairs Mitochondrial Function and Exacerbates Heart Failure Progression
Bibliographic record
Abstract
Background: Energy starvation resulting from impaired mitochondrial function is one of the key mechanisms of heart failure development. Emerging evidence shows that lysine acetylation is one of the critical post-translational modifications that modulates mitochondrial bioenergetic output. We have identified General Control of Amino-Acid Synthesis 5-like 1 (GCN5L1) as a key acetyltransferase protein responsible for dynamic mitochondrial protein acetylation, and that this mechanism plays an essential role in regulating fatty acid oxidation. However, the role of GCN5L1 regulation on mitochondrial function in heart failure development is unknown. Methods and results: We examined GCN5L1 expression in cultured neonatal cardiac myocytes (RNCM) challenged with hypertrophy inducer phenylepherine (PE), and in failing hearts. We found that GCN5L1 mRNA and protein expression is markedly decreased in RNCM treated with PE, and in heart failure induced by mouse transaortic constriction (TAC). In addition, total mitochondrial protein acetylation in failing hearts was significantly decreased, corresponding to the decreased levels of GCN5L1. Next, we investigated the impact of decreased level of GCN5L1 on mitochondrial function and cardiac function in response to pathological stress. We found that GCN5L1 knockdown by shRNA in RNCM results in a decrease in basal oxygen consumption rate and ATP-linked respiration upon PE stimulation. More importantly, knocking down GCN5L1 in the presence of PE exacerbates the RNCM hypertrophic response assessed by increased cellular area and elevated ANP and BNP. Consistent with these in vitro studies, cardiac specific GCN5L1 knockout mice subjected to TAC display accelerated cardiac hypertrophy and heart failure, compared to WT littermates (fractional shortening 15.7% vs 26.4%, n=6-7 in each group, P < 0.05). Conclusion: GCN5L1 plays a critical role in mitochondrial function and cardiac bioenergetics in response to stress. Impaired GCN5L1 function might be one of the key mechanisms of metabolic derangement in heart failure development, and could be a promising therapeutic target.
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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 | 0.000 | 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".