Abstract 11187: Doxorubicin Provokes Maladaptive Autophagy and Necrotic Cell Death of Cardiac Myocytes by Disrupting Mitochondrial Respiration Chain Complex IV
Bibliographic record
Abstract
Doxorubicin is known for its cardiotoxic effects and inducing cardiac failure, however, the underlying mechanisms remain cryptic. Earlier we established the inducible - death protein, Bcl-2-like Nineteen- Kilodalton- Interacting - Protein 3 (Bnip3) to be crucial for disrupting mitochondrial function and inducing cell death of cardiac myocytes. Whether Bnip3 underlies cardiotoxic effects of doxorubicin toxicity is unknown. Herein we demonstrate a novel signaling pathway that functionally links activation and preferential mitochondrial targeting of Bnip3 to the cardiotoxic properties of doxorubicin. Perturbations to mitochondria were observed in cardiac myocytes treated with doxorubicin. Impaired mitochondrial function was accompanied by an accumulated increase in autophagosomes and necrosis demonstrated by increase release of LDH, cTnT and loss of nuclear High Mobility Group Protein 1 (HMGB-1) immunoreactivity. Notably, mitochondrial associated Bnip3 in cells treated with doxorubicin formed strong protein interactions with Cytochrome c oxidase subunit1 (COX1) of respiratory chain. This displaced uncoupling protein 3 (UCP3) from COX1 resulting in increased ROS production, decline in maximal and reserved respiration capacity and cell viability. Interestingly, inhibition of autophagy with 3-methyl adenine (3-MA), or Atg7 knock-down suppressed doxorubicin induced necrotic cell death. Importantly genetic inhibition of Bnip3 preserved UCP3-COX complexes, mitochondrial respiratory integrity and abrogated doxorubicin induced necrotic cell death. Moreover, Bnip3-/- mice were resistant to doxorubicin cardiotoxicity displaying normal mitochondrial morphology, cardiac function and survival rates comparable to wild type vehicle treated litter mates. In this report, we demonstrate that doxorubicin provokes maladaptive autophagy resulting in necrotic cell death of ventricular myocytes by a mechanism that involves mitochondria dysfunction induced by the Bcl-2 death protein Bnip3.
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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 | 0.000 | 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) | 0.003 | 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".