Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Abstract While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogen...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46384-8 |
| _version_ | 1827310078810652672 |
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| author | Zaher ElBeck Mohammad Bakhtiar Hossain Humam Siga Nikolay Oskolkov Fredrik Karlsson Julia Lindgren Anna Walentinsson Dominique Koppenhöfer Rebecca Jarvis Roland Bürli Tanguy Jamier Elske Franssen Mike Firth Andrea Degasperi Claus Bendtsen Robert I. Menzies Katrin Streckfuss-Bömeke Michael Kohlhaas Alexander G. Nickel Lars H. Lund Christoph Maack Ákos Végvári Christer Betsholtz |
| author_facet | Zaher ElBeck Mohammad Bakhtiar Hossain Humam Siga Nikolay Oskolkov Fredrik Karlsson Julia Lindgren Anna Walentinsson Dominique Koppenhöfer Rebecca Jarvis Roland Bürli Tanguy Jamier Elske Franssen Mike Firth Andrea Degasperi Claus Bendtsen Robert I. Menzies Katrin Streckfuss-Bömeke Michael Kohlhaas Alexander G. Nickel Lars H. Lund Christoph Maack Ákos Végvári Christer Betsholtz |
| author_sort | Zaher ElBeck |
| collection | DOAJ |
| description | Abstract While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity. We unveil redox-dependent sex dimorphism, and extensive mutual regulation of the antioxidative activities of IDH2 and NRF2 by a feedforward network that involves 2-oxoglutarate and L-2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. Consequently, conditional targeting of ROS in a murine model of heart failure improves cardiac function in sex- and phenotype-dependent manners. Together, these insights may explain why previous attempts to treat heart failure with antioxidants have been unsuccessful and open new approaches to personalizing and, thereby, improving such treatment. |
| first_indexed | 2024-04-24T19:54:00Z |
| format | Article |
| id | doaj.art-8cb734f3e6db454ca663dbe7df2cc0bb |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T19:54:00Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8cb734f3e6db454ca663dbe7df2cc0bb2024-03-24T12:27:04ZengNature PortfolioNature Communications2041-17232024-03-0115112310.1038/s41467-024-46384-8Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent mannerZaher ElBeck0Mohammad Bakhtiar Hossain1Humam Siga2Nikolay Oskolkov3Fredrik Karlsson4Julia Lindgren5Anna Walentinsson6Dominique Koppenhöfer7Rebecca Jarvis8Roland Bürli9Tanguy Jamier10Elske Franssen11Mike Firth12Andrea Degasperi13Claus Bendtsen14Robert I. Menzies15Katrin Streckfuss-Bömeke16Michael Kohlhaas17Alexander G. Nickel18Lars H. Lund19Christoph Maack20Ákos Végvári21Christer Betsholtz22Department of Medicine Huddinge, Karolinska Institutet, Campus FlemingsbergBioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaDepartment of Medicine Huddinge, Karolinska Institutet, Campus FlemingsbergDepartment of Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Lund UniversityData Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZenecaTranslational Genomics, Centre for Genomics Research, Discovery Sciences, R&D, AstraZenecaTranslational Science & Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaDepartment of Medicine Huddinge, Karolinska Institutet, Campus FlemingsbergNeuroscience, BioPharmaceuticals R&D, AstraZenecaNeuroscience, BioPharmaceuticals R&D, AstraZenecaNeuroscience, BioPharmaceuticals R&D, AstraZenecaNeuroscience, BioPharmaceuticals R&D, AstraZenecaData Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZenecaData Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZenecaData Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZenecaBioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaInstitute of Pharmacology and Toxicology, University of WürzburgDepartment of Translational Research, Comprehensive Heart Failure Center (CHFC), University Clinic WürzburgDepartment of Translational Research, Comprehensive Heart Failure Center (CHFC), University Clinic WürzburgDepartment of Medicine Karolinska Institutet, and Department of Cardiology, Karolinska University HospitalDepartment of Translational Research, Comprehensive Heart Failure Center (CHFC), University Clinic WürzburgDivision of Chemistry I, Department of Medical Biochemistry & Biophysics, Karolinska InstitutetDepartment of Medicine Huddinge, Karolinska Institutet, Campus FlemingsbergAbstract While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity. We unveil redox-dependent sex dimorphism, and extensive mutual regulation of the antioxidative activities of IDH2 and NRF2 by a feedforward network that involves 2-oxoglutarate and L-2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. Consequently, conditional targeting of ROS in a murine model of heart failure improves cardiac function in sex- and phenotype-dependent manners. Together, these insights may explain why previous attempts to treat heart failure with antioxidants have been unsuccessful and open new approaches to personalizing and, thereby, improving such treatment.https://doi.org/10.1038/s41467-024-46384-8 |
| spellingShingle | Zaher ElBeck Mohammad Bakhtiar Hossain Humam Siga Nikolay Oskolkov Fredrik Karlsson Julia Lindgren Anna Walentinsson Dominique Koppenhöfer Rebecca Jarvis Roland Bürli Tanguy Jamier Elske Franssen Mike Firth Andrea Degasperi Claus Bendtsen Robert I. Menzies Katrin Streckfuss-Bömeke Michael Kohlhaas Alexander G. Nickel Lars H. Lund Christoph Maack Ákos Végvári Christer Betsholtz Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner Nature Communications |
| title | Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner |
| title_full | Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner |
| title_fullStr | Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner |
| title_full_unstemmed | Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner |
| title_short | Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner |
| title_sort | epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex dependent manner |
| url | https://doi.org/10.1038/s41467-024-46384-8 |
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