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      Effects of doxorubicin‐induced cardiotoxicity on cardiac mitochondrial dynamics and mitochondrial function: Insights for future interventions

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          Abstract

          Anthracyclines is an effective chemotherapeutic treatment used for many types of cancer. However, high cumulative dosage of anthracyclines leads to cardiac toxicity and heart failure. Dysregulation of mitochondrial dynamics and function are major pathways driving this toxicity. Several pharmacological and non‐pharmacological interventions aiming to attenuate cardiac toxicity by targeting mitochondrial dynamics and function have shown beneficial effects in cell and animal models. However, in clinical practice, there is currently no standard therapy for the prevention of anthracycline‐induced cardiotoxicity. This review summarizes current reports on the impact of anthracyclines on cardiac mitochondrial dynamics and mitochondrial function and potential interventions targeting these pathways. The roles of mitochondrial dynamics and mitochondrial function in the development of anthracycline‐induced cardiotoxicity should provide insights in devising novel strategies to attenuate the cardiac toxicity induced by anthracyclines.

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          Most cited references83

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          Mitochondrial dynamics--mitochondrial fission and fusion in human diseases.

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            Reactive oxygen species and mitochondria: A nexus of cellular homeostasis

            Reactive oxygen species (ROS) are integral components of multiple cellular pathways even though excessive or inappropriately localized ROS damage cells. ROS function as anti-microbial effector molecules and as signaling molecules that regulate such processes as NF-kB transcriptional activity, the production of DNA-based neutrophil extracellular traps (NETs), and autophagy. The main sources of cellular ROS are mitochondria and NADPH oxidases (NOXs). In contrast to NOX-generated ROS, ROS produced in the mitochondria (mtROS) were initially considered to be unwanted by-products of oxidative metabolism. Increasing evidence indicates that mtROS have been incorporated into signaling pathways including those regulating immune responses and autophagy. As metabolic hubs, mitochondria facilitate crosstalk between the metabolic state of the cell with these pathways. Mitochondria and ROS are thus a nexus of multiple pathways that determine the response of cells to disruptions in cellular homeostasis such as infection, sterile damage, and metabolic imbalance. In this review, we discuss the roles of mitochondria in the generation of ROS-derived anti-microbial effectors, the interplay of mitochondria and ROS with autophagy and the formation of DNA extracellular traps, and activation of the NLRP3 inflammasome by ROS and mitochondria.
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              Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1.

              Heme oxygenase (HO)-1 is a protective antioxidant enzyme that prevents cardiomyocyte apoptosis, for instance, during progressive cardiomyopathy. Here we identify a fundamental aspect of the HO-1 protection mechanism by demonstrating that HO-1 activity in mouse heart stimulates the bigenomic mitochondrial biogenesis program via induction of NF-E2-related factor (Nrf)2 gene expression and nuclear translocation. Nrf2 upregulates the mRNA, protein, and activity for HO-1 as well as mRNA and protein for nuclear respiratory factor (NRF)-1. Mechanistically, in cardiomyocytes, endogenous carbon monoxide (CO) generated by HO-1 overexpression stimulates superoxide dismutase-2 upregulation and mitochondrial H(2)O(2) production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3beta, which permits Nrf2 nuclear translocation and occupancy of 4 antioxidant response elements (AREs) in the NRF-1 promoter. The ensuing accumulation of nuclear NRF-1 protein leads to gene activation for mitochondrial biogenesis, which opposes apoptosis and necrosis caused by the cardio-toxic anthracycline chemotherapeutic agent, doxorubicin. In cardiac cells, Akt silencing exacerbates doxorubicin-induced apoptosis, and in vivo CO rescues wild-type but not Akt1(-/-) mice from doxorubicin cardiomyopathy. These findings consign HO-1/CO signaling through Nrf2 and Akt to the myocardial transcriptional program for mitochondrial biogenesis, provide a rationale for targeted mitochondrial CO therapy, and connect cardiac mitochondrial volume expansion with the inducible network of xenobiotic and antioxidant cellular defenses.
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                Author and article information

                Contributors
                nchattip@gmail.com
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                26 April 2020
                June 2020
                : 24
                : 12 ( doiID: 10.1111/jcmm.v24.12 )
                : 6534-6557
                Affiliations
                [ 1 ] Division of Cardiology Department of Internal Medicine Faculty of Medicine Chiang Mai University Chiang Mai Thailand
                [ 2 ] Cardiac Electrophysiology Research and Training Center Faculty of Medicine Chiang Mai University Chiang Mai Thailand
                [ 3 ] Center of Excellence in Cardiac Electrophysiology Research Chiang Mai University Chiang Mai Thailand
                [ 4 ] Cardiac Electrophysiology Unit Department of Physiology Faculty of Medicine Chiang Mai University Chiang Mai Thailand
                Author notes
                [*] [* ] Correspondence

                Nipon Chattipakorn, Faculty of Medicine, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai 50200, Thailand.

                Email: nchattip@ 123456gmail.com

                Author information
                https://orcid.org/0000-0003-3026-718X
                Article
                JCMM15305
                10.1111/jcmm.15305
                7299722
                32336039
                eb99ce33-0245-4eab-a9e3-661387ad8501
                © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 June 2019
                : 30 August 2019
                : 17 September 2019
                Page count
                Figures: 2, Tables: 4, Pages: 24, Words: 11328
                Funding
                Funded by: National Science and Technology Development Agency , open-funder-registry 10.13039/501100004192;
                Award ID: Research Chair Grant (NC)
                Funded by: Thailand Research Fund , open-funder-registry 10.13039/501100004396;
                Award ID: RTA6080003 (SCC)
                Funded by: Chiang Mai University , open-funder-registry 10.13039/501100002842;
                Award ID: Center of Excellence Award (NC)
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                June 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:17.06.2020

                Molecular medicine
                cardiotoxicity,doxorubicin,mitochondrial dynamics,mitochondrial function
                Molecular medicine
                cardiotoxicity, doxorubicin, mitochondrial dynamics, mitochondrial function

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