Abstract 15546: Loss of Mitochondrial UCP3-Cytochrome c Oxidase Complexes Underlies Maladaptive Autophagy and Cardiac Failure in Anthracycline Cardiotoxicity
Bibliographic record
Abstract
Doxorubicin is known for its cardiotoxic effects and inducing cardiac failure. Herein we demonstrate a novel signaling pathway that functionally links activation and preferential mitochondrial targeting of Bnip3 to doxorubicin cardiotoxicity. Perturbations to mitochondria including increased calcium, ROS, loss of αΨm and mPTP opening were observed in cardiac myocytes treated with doxorubicin. This coincided with a decline in maximal respiratory capacity, loss of respiratory chain complexes of uncoupling protein 3 (UCP3) and cytochrome c oxidase complex IV subunit 1, (COX) and cell viability. 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. Interestingly, pharmacological or genetic inhibition of autophagy with 3-methyl adenine (3-MA), or Atg7 knock-down suppressed necrotic cell death induced by doxorubicin. Conversely, loss of function of Bnip3 or mutations of Bnip3 defective for mitochondrial targeting restored UCP3-COX complexes, mitochondrial respiratory integrity and suppressed necrotic cell death induced by doxorubicin. Finally, mice germ-line deficient for Bnip3 were resistant to the cytotoxic effects of doxorubicin displaying mitochondrial morphology, cardiac function and survival rates comparable to vehicle treated control mice. To our knowledge the findings of the present study provide the first direct evidence that doxorubicin triggers maladaptive autophagy and necrotic cell death of ventricular myocytes by a mechanism mutually dependent and obligatorily linked to Bnip3. Hence, therapeutic interventions to selectively inhibit Bnip3 may prove beneficial in suppressing mitochondrial injury and heart failure in cancer patients undergoing doxorubicin treatment.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".