Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q.

Doxorubicin (DOX) is used for treating various cancers. Its clinical use is, however, limited by its dose-limiting cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy still remains unknown. The goals were to investigate the molecular mechanism of DOX-induced cardiomyopathy and cardioprotection by mitoquinone (Mito-Q), a triphenylphosphonium-conjugated analog of coenzyme Q, using a rat model. Rats were treated with DOX, Mito-Q, and DOX plus Mito-Q for 12 weeks. The left ventricular function as measured by two-dimensional echocardiography decreased in DOX-treated rats but was preserved during Mito-Q plus DOX treatment. Using low-temperature ex vivo electron paramagnetic resonance (EPR), a time-dependent decrease in heme signal was detected in heart tissues isolated from rats administered with a cumulative dose of DOX. DOX attenuated the EPR signals characteristic of the exchange interaction between cytochrome c oxidase (CcO)-Fe(III) heme a3 and CuB. DOX and Mito-Q together restored these EPR signals and the CcO activity in heart tissues. DOX strongly downregulated the stable expression of the CcO subunits II and Va and had a slight inhibitory effect on CcO subunit I gene expression. Mito-Q restored CcO subunit II and Va expressions in DOX-treated rats. These results suggest a novel cardioprotection mechanism by Mito-Q during DOX-induced cardiomyopathy involving CcO.

• Publication year

  2009

• Venue

  Biophysical Journal

• Publication date

  2009-02-18

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.bpj.2008.10.042PMID 19217856PMCID PMC2717244
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Early detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography.

  2008influential reference
• Targeting antioxidants to mitochondria by conjugation to lipophilic cations.

  2007cited by this paper
• Dexrazoxane prevents doxorubicin‐induced long‐term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats

  2007cited by this paper
• Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes

  2007cited by this paper
• Filling the Catalytic Site of Cytochrome c Oxidase with Electrons

  2006cited by this paper
• Anthracycline-Induced Cardiotoxicity in Children with Cancer

  2005cited by this paper
• Modulation of Cytochrome c Oxidase-Va Is Possibly Involved in Metallothionein Protection from Doxorubicin Cardiotoxicity

  2005influential reference
• Coenzyme Q10 for Prevention of Anthracycline-Induced Cardiotoxicity

  2005cited by this paper
• Interactions of Mitochondria-targeted and Untargeted Ubiquinones with the Mitochondrial Respiratory Chain and Reactive Oxygen Species

  2005cited by this paper
• Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia.

  2005cited by this paper
• Mitochondria superoxide dismutase mimetic inhibits peroxide-induced oxidative damage and apoptosis: role of mitochondrial superoxide.

  2005cited by this paper
• Chemotherapy and cardiotoxicity in older breast cancer patients: a population-based study.

  2005cited by this paper
• Evidence for Electron Equilibrium between the Two Hemes bL in the Dimeric Cytochrome bc1 Complex*

  2005cited by this paper
• Tissue‐specific mtDNA lesions and radical‐associated mitochondrial dysfunction in human hearts exposed to doxorubicin

  2005cited by this paper
• Fine‐tuning the hydrophobicity of a mitochondria‐targeted antioxidant

  2004influential reference
• The nature of the exchange coupling between high-spin Fe(III) heme o3 and CuBII in Escherichia coli quinol oxidase, cytochrome bo3: MCD and EPR studies.

  2004cited by this paper
• Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase

  2003cited by this paper
• Late anthracycline cardiotoxicity after childhood cancer

  2003cited by this paper
• Nitric oxide inhibits H2O2-induced transferrin receptor-dependent apoptosis in endothelial cells: Role of ubiquitin-proteasome pathway

  2003cited by this paper
• Doxorubicin-induced cardiac mitochondrionopathy.

  2003cited by this paper
• Time-Dependent and Tissue-Specific Accumulation of mtDNA and Respiratory Chain Defects in Chronic Doxorubicin Cardiomyopathy

  2003cited by this paper
• Cytochrome c Oxidase Subunit III

  2002cited by this paper
• Alterations in the expression of cytochrome c oxidase subunits in doxorubicin-resistant leukemia K562 cells.

  2002cited by this paper
• Doxorubicin-induced apoptosis: Implications in cardiotoxicity

  2002cited by this paper
• Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients

  2002cited by this paper
• Anthracycline-induced cardiotoxicity.

  2000influential reference
• Angular dependences of perpendicular and parallel mode electron paramagnetic resonance of oxidized beef heart cytochrome c oxidase.

  2000influential reference
• Doxorubicin-induced Apoptosis in Endothelial Cells and Cardiomyocytes Is Ameliorated by Nitrone Spin Traps and Ebselen

  2000cited by this paper
• Tissue variant effects of heme inhibitors on the mouse cytochrome c oxidase gene expression and catalytic activity of the enzyme complex.

  1999cited by this paper
• Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane.

  1999cited by this paper
• Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene

  1999cited by this paper
• Structural and functional impairment of mitochondria in adriamycin-induced cardiomyopathy in mice: suppression of cytochrome c oxidase II gene expression.

  1999cited by this paper
• Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: the role of reactive oxygen and nitrogen intermediates.

  1999cited by this paper
• Doxorubicin-induced cardiomyopathy.

  1998cited by this paper
• A small animal model of non-ischemic cardiomyopathy and its evaluation by transthoracic echocardiography.

  1998cited by this paper
• Apoptosis: basic mechanisms and implications for cardiovascular disease.

  1998cited by this paper
• Anthracycline-Induced Cardiotoxicity

  1996cited by this paper
• Cytoprotective agents for anthracyclines.

  1996cited by this paper
• Measuring nitric oxide and superoxide: rate constants for aconitase reactivity.

  1996cited by this paper
• Visualization of doxorubicin-induced oxidative stress in isolated cardiac myocytes.

  1996cited by this paper
• Structure at 2.8 Å resolution of cytochrome c oxidase from Paracoccus denitrificans

  1995cited by this paper
• Structures of metal sites of oxidized bovine heart cytochrome c oxidase at 2.8 A

  1995influential reference
• Identification of a novel quinone-binding site in the cytochrome bo complex from Escherichia coli.

  1994cited by this paper
• Mitochondrial cytochrome c oxidase as a target site for daunomycin in K-562 cells and heart tissue.

  1993cited by this paper
• Characterization of a novel g' = 2.95 EPR signal from the binuclear center of mitochondrial cytochrome c oxidase.

  1992cited by this paper
• The iron-sulfur clusters in the two related forms of mitochondrial NADH: ubiquinone oxidoreductase made by Neurospora crassa.

  1991cited by this paper
• Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity.

  1990cited by this paper
• Multifrequency EPR evidence for a bimetallic center at the CuA site in cytochrome c oxidase

  1990cited by this paper
• Spatial organization of redox active centers in the bovine heart ubiquinol-cytochrome c oxidoreductase.

  1989cited by this paper
• Relative importance of intracellular glutathione peroxidase and catalase in vivo for prevention of peroxidation to the heart.

  1989cited by this paper
• Relative importance of intracellular glutathione peroxidase and catalase in vivo for prevention of peroxidation to the heart.

  1989cited by this paper
• Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase.

  1986cited by this paper
• Doxorubicin cardiotoxicity: contractile changes after long-term treatment in the rat.

  1986cited by this paper
• Clinical spectrum of anthracycline antibiotic cardiotoxicity.

  1978cited by this paper
• Adriamycin (NSC 123127) cardiomyopathy. An overview with determination of risk factors

  1975cited by this paper
• Electron paramagnetic resonance-detectable electron acceptors in beef heart mitochondria. Reduced diphosphopyridine nucleotide ubiquinone reductase segment of the electron transfer system.

  1974cited by this paper
• © 2004 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. Redox Reactions of the Iron-Sulfur Cluster in a Ribosomal RNA

  year unknowncited by this paper

• Deciphering the role of mitochondrial cytochrome C oxidase subunit 4 in cardiac health and disease.

  2026cites this paper
• Oxphos targeting of MYCN-amplified neuroblastoma

  2025cites this paper
• Understanding the Mechanisms of Chemotherapy-Related Cardiotoxicity Employing hiPSC-Derived Cardiomyocyte Models for Drug Screening and the Identification of Genetic and Epigenetic Variants

  2025cites this paper
• The Application and Molecular Mechanisms of Mitochondria-Targeted Antioxidants in Chemotherapy-Induced Cardiac Injury

  2025cites this paper
• Metabolic Reprogramming in Cancer Therapy-Related Cardiovascular Toxicity: Mechanisms and Intervention Strategies.

  2025cites this paper
• Low Molecular Weight Modifications of Anthracycline Antibiotics. Part I. Reactions by Amino Group (A Review)

  2024cites this paper
• Molecular effects of polystyrene nanoplastics on human neural stem cells

  2024cites this paper
• Carvedilol Phenocopies PGC-1α Overexpression to Alleviate Oxidative Stress, Mitochondrial Dysfunction and Prevent Doxorubicin-Induced Toxicity in Human iPSC-Derived Cardiomyocytes

  2023cites this paper
• Redox-crippled MitoQ potently inhibits breast cancer and glioma cell proliferation: A negative control for verifying the antioxidant mechanism of MitoQ in cancer and other oxidative pathologies

  2023cites this paper
• Vernonia amygdalina Ethanol Extract Protects against Doxorubicin-Induced Cardiotoxicity via TGFβ, Cytochrome c, and Apoptosis

  2023cites this paper
• Mitochondria-Targeted Antioxidants as a Therapeutic Strategy for Chronic Obstructive Pulmonary Disease

  2023cites this paper
• Endothelial-to-Mesenchymal Transition: Potential Target of Doxorubicin-Induced Cardiotoxicity

  2023cites this paper
• Hypoxia Inhibitor Combined with Chemotherapeutic Agents for Antitumor and Antimetastatic Efficacy against Osteosarcoma.

  2023cites this paper
• Low-Dose Radiation Reduces Doxorubicin-Induced Myocardial Injury Through Mitochondrial Pathways

  2023cites this paper
• Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?

  2023cites this paper
• Mitochondrial quality control in health and cardiovascular diseases

  2023cites this paper
• OXPHOS-targeting drugs in oncology: new perspectives

  2023cites this paper
• Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications

  2023cites this paper
• Doxorubicin cardiotoxicity and Camellia sinensis cardioprotection determined by speckle-tracking echocardiography

  2023cites this paper
• Mitochondrial Quality Control Mechanisms during Diabetic Cardiomyopathy

  2022cites this paper
• Heart Failure

  2022cites this paper
• PET Tracers for Imaging Cardiac Function in Cardio-oncology

  2022cites this paper
• Understanding Anthracycline Cardiotoxicity From Mitochondrial Aspect

  2022cites this paper
• Mitochondrial-Targeted Therapy for Doxorubicin-Induced Cardiotoxicity

  2022cites this paper
• Targeting mitochondrial metabolism for precision medicine in cancer

  2022cites this paper
• Thymoquinone Prevents Doxorubicin-induced Hepatic-injury by Mitigating the Impairment of Mitochondrial Respiration and Electron Transport

  2022cites this paper
• Doxorubicin-Induced Cardiotoxicity: Mechanisms and Management

  2022cites this paper
• Molecular effects of polystyrene nanoplastics toxicity in zebrafish embryos (Daniorerio).

  2022cites this paper
• The Role of Mitochondrial Quality Control in Anthracycline-Induced Cardiotoxicity: From Bench to Bedside

  2022cites this paper
• Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

  2021cites this paper
• Hypoxia signaling and oxygen metabolism in cardio-oncology.

  2021cites this paper
• Mitochondria-Targeted Antioxidants and Cancer

  2021cites this paper
• Mitoquinol mesylate (MITOQ) attenuates diethyl nitrosamine-induced hepatocellular carcinoma through modulation of mitochondrial antioxidant defense systems

  2021cites this paper
• Melatonin Alleviates Cardiac Function in Sepsis-Caused Myocarditis via Maintenance of Mitochondrial Function

  2021cites this paper
• Actions and Therapeutic Potential of Madecassoside and Other Major Constituents of Centella asiatica: A Review

  2021cites this paper
• Subclinical doxorubicin-induced cardiotoxicity update: role of neutrophils and endothelium.

  2021cites this paper
• Mitochondrial targeted antioxidants, mitoquinone and SKQ1, not vitamin C, mitigate doxorubicin-induced damage in H9c2 myoblast: pretreatment vs. co-treatment

  2021cites this paper
• Natural and synthetic antioxidants targeting cardiac oxidative stress and redox signaling in cardiometabolic diseases.

  2021cites this paper
• In vivo/Ex Vivo EPR Investigation of the Brain Redox Status and Blood--Brain Barrier Integrity in the 5xFAD Mouse Model of Alzheimer's Disease.

  2021cites this paper
• Sepsis-induced myocardial dysfunction: the role of mitochondrial dysfunction

  2021cites this paper
• Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice

  2021cites this paper
• Role of IRE1α in podocyte proteostasis and mitochondrial health

  2020cites this paper
• Riding the tiger – physiological and pathological effects of superoxide and hydrogen peroxide generated in the mitochondrial matrix

  2020cites this paper
• Doxorubicin-Induced Oxidative Stress and Endothelial Dysfunction in Conduit Arteries Is Prevented by Mitochondrial-Specific Antioxidant Treatment

  2020cites this paper
• Acyl-CoA thioesterase 1 prevents cardiomyocytes from Doxorubicin-induced ferroptosis via shaping the lipid composition

  2020cites this paper
• Overexpression of COX5A protects H9c2 cells against doxorubicin-induced cardiotoxicity.

  2020cites this paper
• Mitoquinone (MitoQ) Inhibits Platelet Activation Steps by Reducing ROS Levels

  2020cites this paper
• Effect of Pretreatment of Aerobic Training on Doxorubicin- induced Left Ventricular Apoptosis Gene Expression in Aging Rat Model

  2020cites this paper
• Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI

  2020cites this paper
• Mitochondrial Determinants of Doxorubicin-Induced Cardiomyopathy.

  2020cites this paper
• Ameliorative effect of Dillenia indica fruits against doxorubicin-induced cardiomyocyte toxicity

  2020cites this paper
• Cryogenic electron paramagnetic resonance spectroscopy of flash-frozen tissue for characterization of mitochondrial disease

  2020cites this paper
• Ameliorative effect of Dillenia indica fruits against doxorubicin-induced cardiomyocyte toxicity

  2020cites this paper
• The role of mitochondrial dynamics in cardiovascular diseases

  2020cites this paper
• Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI

  2020cites this paper
• Mitochondrially-targeted treatment strategies.

  2019cites this paper
• Sirt3‐dependent deacetylation of COX‐1 counteracts oxidative stress‐induced cell apoptosis

  2019cites this paper
• Electronation‐dependent structural change at the proton exit side of cytochrome c oxidase as revealed by site‐directed fluorescence labeling

  2019cites this paper
• Intracellular Microenvironment Triggered Co-delivery of Anticancer Drugs and Genes

  2019influential citation
• Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis

  2019cites this paper
• Mitochondrial complex I deficiency and cardiovascular diseases: current evidence and future directions

  2019cites this paper
• Full Issue PDF

  2019cites this paper
• Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree?

  2019influential citation
• Low-Temperature EPR Spectroscopy as a Probe-Free Technique for Monitoring Oxidants Formed in Tumor Cells and Tissues: Implications in Drug Resistance and OXPHOS-Targeted Therapies

  2018cites this paper
• The effect of melatonin treatment on doxorubicin-induced skeletal muscle atrophy within a cancer model

  2018cites this paper
• In Vivo Reactive Oxygen Species Detection With a Novel Positron Emission Tomography Tracer, 18F-DHMT, Allows for Early Detection of Anthracycline-Induced Cardiotoxicity in Rodents

  2018cites this paper
• Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation

  2018cites this paper
• Calcium Signaling and Reactive Oxygen Species in Mitochondria

  2018cites this paper
• Detection of mitochondria-generated reactive oxygen species in cells using multiple probes and methods: Potentials, pitfalls, and the future

  2018cites this paper
• Platelet mitochondrial dysfunction and mitochondria‐targeted quinone‐and hydroquinone‐derivatives: Review on new strategy of antiplatelet activity

  2018cites this paper
• Mitochondria targeting and its consequences for cell death in neuroblastoma

  2018cites this paper
• Drug‐Induced Mitochondrial Cardiomyopathy and Cardiovascular Risks in Children

  2018cites this paper
• Placental Adaptation to Early-Onset Hypoxic Pregnancy and Mitochondria-Targeted Antioxidant Therapy in a Rodent Model

  2018cites this paper
• Mitochondria as a therapeutic target for common pathologies

  2018cites this paper
• Cardiac and Mitochondrial Adaptations in Response to Aging and Doxorubicin in Rats Bred for Divergent Aerobic Capacities

  2017cites this paper
• Mitochondrial Therapies in Heart Failure.

  2017cites this paper
• Oxidative stress and inflammation as central mediators of atrial fibrillation in obesity and diabetes

  2017cites this paper
• Modified Metformin as a More Potent Anticancer Drug: Mitochondrial Inhibition, Redox Signaling, Antiproliferative Effects and Future EPR Studies

  2017cites this paper
• Antioxidants Protect against Arsenic Induced Mitochondrial Cardio-Toxicity

  2017cites this paper
• Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells

  2017cites this paper
• MicroRNA-34a Encapsulated in Hyaluronic Acid Nanoparticles Induces Epigenetic Changes with Altered Mitochondrial Bioenergetics and Apoptosis in Non-Small-Cell Lung Cancer Cells

  2017cites this paper
• Targeting Mitochondrial Calcium Handling and Reactive Oxygen Species in Heart Failure

  2017cites this paper
• Reduction of Doxorubicin-Induced Cardiotoxicity Using Nanocarriers: A Review.

  2017cites this paper
• Mitochondrial dysfunction and mitochondrial dynamics-The cancer connection.

  2017cites this paper
• The Effect of Regular Aerobic Exercise with Garlic Extract on Heart Apoptosis Regulatory Factors in Chronic Kidney Disease

  2017cites this paper
• Heart Failure in Pediatric Oncologic Disease

  2017cites this paper
• Acute and chronic effects of anti-cancer agents on cardiac mitochondrial function

  2017influential citation
• Rol de la función mitocondrial en el corazón y sus implicaciones en disfunciones cardíacas

  2017cites this paper
• Protective effects of dioscin against doxorubicin-induced nephrotoxicity via adjusting FXR-mediated oxidative stress and inflammation.

  2017cites this paper
• The role of oxidative stress in the crosstalk between leptin and mineralocorticoid receptor in the cardiac fibrosis associated with obesity

  2017cites this paper
• Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications.

  2017cites this paper
• Mitochondria-Targeted Antioxidants for the Treatment of Cardiovascular Disorders.

  2017cites this paper
• Cardiac metabolism — A promising therapeutic target for heart failure

  2017cites this paper
• Energy Remodeling, Mitochondrial Disorder and Heart Failure.

  2016cites this paper
• Iron-sulfur cluster damage by the superoxide radical in neural tissues of the SOD1(G93A) ALS rat model.

  2016influential citation
• Targeting Mitochondrial Dysfunction in Chronic Heart Failure: Current Evidence and Potential Approaches.

  2016cites this paper
• The Role of Mitochondrial Dysfunction in Heart Failure and Potential Therapeutic Targets.

  2016cites this paper
• Cardiomyocytes – Active Players in Cardiac Disease

  2016cites this paper
• Turning the gun on cancer: Utilizing lysosomal P-glycoprotein as a new strategy to overcome multi-drug resistance.

  2016cites this paper
• Targeting Mitochondria in Cardiovascular Diseases.

  2016cites this paper