ArticleProceedings of the National Academy of Sciences of the United States of America2014
Bnip3 mediates doxorubicin-induced cardiac myocyte necrosis and mortality through changes in mitochondrial signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 122 papers.
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122 citing papers in PubMed, 217 citations in OpenAlex.
- Priming of human iPSCs with doxorubicin causes genome-wide transcriptional reprogramming and functional impairments in iPSC-derived cardiomyocytes.NPJ Regenerative medicine · 2026Article
- Mechanisms and Therapeutic Potential of Targeting Mitophagy in Neurodegenerative Diseases.Molecular neurobiology · 2026Review
- Molecular diversity of mitochondrial autophagy receptors: context-dependent effects in human health and disease.Cell death discovery · 2026Review
- Reverse engineering of BNIP3 identifies a mitochondrial protective peptide.Nature communications · 2026Article
- Effects of high-intensity aerobic exercise during multiple cycles of doxorubicin treatment on cardiac catabolism.Physical activity and nutrition · 2026Article
- Peroxiredoxin Ⅲ safeguards cardiac function against doxorubicin by regulating mitochondrial quality control via HRedox biology · 2026Article
- Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.Circulation research · 2026Review
- Chemo-/radiotherapy-induced cardiomyopathy: roles of mitochondria and endoplasmic reticulum.Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] · 2026Review
- Doxorubicin-Induced Cardiac Remodeling: Mechanisms and Mitigation Strategies.Cardiovascular drugs and therapy · 2026Review
- Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review).International journal of molecular medicine · 2025Review
- BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation.Autophagy · 2025Article
- Mitochondrial quality control as a therapeutic target in cardiovascular disease: Mechanistic insights and future directions.Journal of translational internal medicine · 2025Article
- Doxorubicin-Induced Cardiotoxicity: A Comprehensive Update.Journal of cardiovascular development and disease · 2025Review
- New insights into mitochondrial quality control in anthracycline-induced cardiotoxicity: molecular mechanisms, therapeutic targets, and natural products.International journal of biological sciences · 2025Review
- Translationally controlled tumor protein interacts with connexin 43 and facilitates intercellular coupling between cardiomyocytes.Frontiers in cell and developmental biology · 2025Article
- The multifaceted role of autophagy and mitophagy in cardiovascular health and disease.Autophagy reports · 2025Review
- Mitophagy in Doxorubicin-Induced Cardiotoxicity: Insights into Molecular Biology and Novel Therapeutic Strategies.Biomolecules · 2024Review
- Mitochondrial fatty acid oxidation drives senescence.Science advances · 2024Article
- Investigating the interplay between mitophagy and diabetic neuropathy: Uncovering the hidden secrets of the disease pathology.Pharmacological research · 2024Review
- The Abl1 tyrosine kinase is a key player in doxorubicin-induced cardiomyopathy and its p53/p73 cell death mediated signaling differs in atrial and ventricular cardiomyocytes.Journal of translational medicine · 2024Article
62 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 3 countries.
Funding
Abstract
Doxorubicin (DOX) is widely used for treating human cancers, but can induce heart failure through an undefined mechanism. Herein we describe a previously unidentified signaling pathway that couples DOX-induced mitochondrial respiratory chain defects and necrotic cell death to the BH3-only protein Bcl-2-like 19 kDa-interacting protein 3 (Bnip3). Cellular defects, including vacuolization and disrupted mitochondria, were observed in DOX-treated mice hearts. This coincided with mitochondrial localization of Bnip3, increased reactive oxygen species production, loss of mitochondrial membrane potential, mitochondrial permeability transition pore opening, and necrosis. Interestingly, a 3.1-fold decrease in maximal mitochondrial respiration was observed in cardiac mitochondria of mice treated with DOX. In vehicle-treated control cells undergoing normal respiration, the respiratory chain complex IV subunit 1 (COX1) was tightly bound to uncoupling protein 3 (UCP3), but this complex was disrupted in cells treated with DOX. Mitochondrial dysfunction induced by DOX was accompanied by contractile failure and necrotic cell death. Conversely, shRNA directed against Bnip3 or a mutant of Bnip3 defective for mitochondrial targeting abrogated DOX-induced loss of COX1-UCP3 complexes and respiratory chain defects. Finally, Bnip3(-/-) mice treated with DOX displayed relatively normal mitochondrial morphology, respiration, and mortality rates comparable to those of saline-treated WT mice, supporting the idea that Bnip3 underlies the cardiotoxic effects of DOX. These findings reveal a new signaling pathway in which DOX-induced mitochondrial respiratory chain defects and necrotic cell death are mutually dependent on and obligatorily linked to Bnip3 gene activation. Interventions that antagonize Bnip3 may prove beneficial in preventing mitochondrial injury and heart failure in cancer patients undergoing chemotherapy.
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