Mitochondrial Protein Hyperacetylation in Rodents with Doxorubicin‐Induced Cardiac Dysfunction
Bibliographic record
Abstract
Objective Doxorubicin (DOX) is an effective chemotherapeutic but has dose‐dependent cardiotoxic effects that limits its use in pediatric patients. Previous studies in our lab showed that DOX decreases expression of the mitochondrial lysine deacetylase SIRT3 and mitochondrial phospholipid cardiolipin (CL) in the mouse heart. We hypothesize that DOX impairs cardiac function as a consequence of reduced SIRT3 expression resulting in increased acetylation of mitochondrial proteins involved in cardiac energy and oxidative stress homeostasis. Methods C57BL6 mice were given DOX (8.0mg/kg body weight) or saline control injections for 4 weeks. Transthoracic echocardiography was performed on all mice (n=10 per group) and parameters of cardiac structure, systolic and diastolic function were measured. Cardiac mitochondria were isolated from saline and DOX mice and an anti‐acetylated lysine antibody was used to enrich for tryptic digested peptides containing acetylated lysines followed by mass spectroscopy analysis (n=6). Results DOX treated mice exhibit decreased left ventricular posterior wall thickness (P<0.05), increased intraventricular relaxation time and reduced ejection fraction, compared to controls (P<0.05). Quantitative PCR of cardiolipin biosynthesis genes revealed Ptpmt1 and Crls1 gene expression was reduced by half with DOX compared to controls (p<0.01). In DOX treated mice, we observed an enrichment of cardiac mitochondrial acetylated peptides of proteins involved in metabolic, CL remodelling processes and oxidative stress resistance (eg. ATP5F1A, TFEα, SOD2, P<0.05, >2‐fold increase). MitoSOX staining of human induced pluripotent stem cell derived cardiomyocytes revealed an increase (2.5‐fold, p<0.001) in reactive oxygen species production with DOX treatment which was attenuated with adenoviral SIRT3 overexpression. Conclusion Alterations to the mitochondrial acetylome may be responsible for DOX‐induced cardiac dysfunction in mice. SIRT3 overexpression attenuates production of reactive oxygen species in human derived cardiomyocytes and SIRT3 may prevent cardiotoxic effects of DOX.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".