Exercise and Doxorubicin Modify Markers of Iron Overload and Cardiolipin Deficiency in Cardiac Mitochondria
Doxorubicin (DOX) is a chemotherapeutic agent highly effective at limiting cancer progression. Despite the efficacy of this anticancer drug, the clinical use of DOX is limited due to cardiotoxicity. The cardiac mitochondria are implicated as the primary target of DOX, resulting in inactivation of el...
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/7689 |
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| author | Ryan N. Montalvo Franccesco P. Boeno Imtiaz M. Dowllah Cesar E. Jacintho Moritz Branden L. Nguyen Vivian Doerr Matthew P. Bomkamp Ashley J. Smuder |
| author_facet | Ryan N. Montalvo Franccesco P. Boeno Imtiaz M. Dowllah Cesar E. Jacintho Moritz Branden L. Nguyen Vivian Doerr Matthew P. Bomkamp Ashley J. Smuder |
| author_sort | Ryan N. Montalvo |
| collection | DOAJ |
| description | Doxorubicin (DOX) is a chemotherapeutic agent highly effective at limiting cancer progression. Despite the efficacy of this anticancer drug, the clinical use of DOX is limited due to cardiotoxicity. The cardiac mitochondria are implicated as the primary target of DOX, resulting in inactivation of electron transport system complexes, oxidative stress, and iron overload. However, it is established that the cardiac mitochondrial subpopulations reveal differential responses to DOX exposure, with subsarcolemmal (SS) mitochondria demonstrating redox imbalance and the intermyofibrillar (IMF) mitochondria showing reduced respiration. In this regard, exercise training is an effective intervention to prevent DOX-induced cardiac dysfunction. Although it is clear that exercise confers mitochondrial protection, it is currently unknown if exercise training mitigates DOX cardiac mitochondrial toxicity by promoting beneficial adaptations to both the SS and IMF mitochondria. To test this, SS and IMF mitochondria were isolated from sedentary and exercise-preconditioned female Sprague Dawley rats exposed to acute DOX treatment. Our findings reveal a greater effect of exercise preconditioning on redox balance and iron handling in the SS mitochondria of DOX-treated rats compared to IMF, with rescue of cardiolipin synthase 1 expression in both subpopulations. These results demonstrate that exercise preconditioning improves mitochondrial homeostasis when combined with DOX treatment, and that the SS mitochondria display greater protection compared to the IMF mitochondria. These data provide important insights into the molecular mechanisms that are in part responsible for exercise-induced protection against DOX toxicity. |
| first_indexed | 2024-03-11T04:17:56Z |
| format | Article |
| id | doaj.art-32604241051144d49818a85b72913b75 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:17:56Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-32604241051144d49818a85b72913b752023-11-17T22:59:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01249768910.3390/ijms24097689Exercise and Doxorubicin Modify Markers of Iron Overload and Cardiolipin Deficiency in Cardiac MitochondriaRyan N. Montalvo0Franccesco P. Boeno1Imtiaz M. Dowllah2Cesar E. Jacintho Moritz3Branden L. Nguyen4Vivian Doerr5Matthew P. Bomkamp6Ashley J. Smuder7Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, USADepartment of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, USADepartment of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, USADepartment of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, USADepartment of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, USADepartment of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, USADepartment of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, USADepartment of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32611, USADoxorubicin (DOX) is a chemotherapeutic agent highly effective at limiting cancer progression. Despite the efficacy of this anticancer drug, the clinical use of DOX is limited due to cardiotoxicity. The cardiac mitochondria are implicated as the primary target of DOX, resulting in inactivation of electron transport system complexes, oxidative stress, and iron overload. However, it is established that the cardiac mitochondrial subpopulations reveal differential responses to DOX exposure, with subsarcolemmal (SS) mitochondria demonstrating redox imbalance and the intermyofibrillar (IMF) mitochondria showing reduced respiration. In this regard, exercise training is an effective intervention to prevent DOX-induced cardiac dysfunction. Although it is clear that exercise confers mitochondrial protection, it is currently unknown if exercise training mitigates DOX cardiac mitochondrial toxicity by promoting beneficial adaptations to both the SS and IMF mitochondria. To test this, SS and IMF mitochondria were isolated from sedentary and exercise-preconditioned female Sprague Dawley rats exposed to acute DOX treatment. Our findings reveal a greater effect of exercise preconditioning on redox balance and iron handling in the SS mitochondria of DOX-treated rats compared to IMF, with rescue of cardiolipin synthase 1 expression in both subpopulations. These results demonstrate that exercise preconditioning improves mitochondrial homeostasis when combined with DOX treatment, and that the SS mitochondria display greater protection compared to the IMF mitochondria. These data provide important insights into the molecular mechanisms that are in part responsible for exercise-induced protection against DOX toxicity.https://www.mdpi.com/1422-0067/24/9/7689heartcardiotoxicityanthracyclineoxidative stresssubsarcolemmalintermyofibrillar |
| spellingShingle | Ryan N. Montalvo Franccesco P. Boeno Imtiaz M. Dowllah Cesar E. Jacintho Moritz Branden L. Nguyen Vivian Doerr Matthew P. Bomkamp Ashley J. Smuder Exercise and Doxorubicin Modify Markers of Iron Overload and Cardiolipin Deficiency in Cardiac Mitochondria International Journal of Molecular Sciences heart cardiotoxicity anthracycline oxidative stress subsarcolemmal intermyofibrillar |
| title | Exercise and Doxorubicin Modify Markers of Iron Overload and Cardiolipin Deficiency in Cardiac Mitochondria |
| title_full | Exercise and Doxorubicin Modify Markers of Iron Overload and Cardiolipin Deficiency in Cardiac Mitochondria |
| title_fullStr | Exercise and Doxorubicin Modify Markers of Iron Overload and Cardiolipin Deficiency in Cardiac Mitochondria |
| title_full_unstemmed | Exercise and Doxorubicin Modify Markers of Iron Overload and Cardiolipin Deficiency in Cardiac Mitochondria |
| title_short | Exercise and Doxorubicin Modify Markers of Iron Overload and Cardiolipin Deficiency in Cardiac Mitochondria |
| title_sort | exercise and doxorubicin modify markers of iron overload and cardiolipin deficiency in cardiac mitochondria |
| topic | heart cardiotoxicity anthracycline oxidative stress subsarcolemmal intermyofibrillar |
| url | https://www.mdpi.com/1422-0067/24/9/7689 |
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