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Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner

ElBeck, Zaher (author)
Uppsala universitet,Karolinska Institutet,Uppsala University,Karolinska Institute,Vaskulärbiologi,Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, S-14157 Huddinge, Sweden
Hossain, Mohammad Bakhtiar (author)
Biosci Renal Res & Early Dev, Cardiovasc Renal & Metab CVRM, BioPharmaceut R&D, AstraZeneca, Gothenburg, Sweden.
Siga, Humam (author)
Karolinska Institute,Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, S-14157 Huddinge, Sweden.
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Oskolkov, Nikolay (author)
Lund University,Lunds universitet,Molekylär cellbiologi,Biologiska institutionen,Naturvetenskapliga fakulteten,Bioinformatik,Forskargrupper vid Lunds universitet,LTH profilområde: Teknik för hälsa,LTH profilområden,Lunds Tekniska Högskola,Molecular Cell Biology,Department of Biology,Faculty of Science,Bioinformatics,Lund University Research Groups,LTH Profile Area: Engineering Health,LTH Profile areas,Faculty of Engineering, LTH,Lund Univ, Dept Biol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Lund, Sweden.
Karlsson, Fredrik (author)
AstraZeneca, R&D, Data Sci & Quantitat Biol, Discovery Sci, Gothenburg, Sweden.
Lindgren, Julia (author)
AstraZeneca, Sweden,Translat Genom Ctr Genom Res, Discovery Sci, R&D, Translat Genom,Ctr Genom Res, Gothenburg, Sweden.
Walentinsson, Anna (author)
Translat Sci & Expt Med, Res & Early Dev Cardiovasc Renal & Metab CVRM, BioPharmaceut R&D, AstraZeneca, Gothenburg, Sweden.
Koppenhöfer, Dominique (author)
Karolinska Institute,Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, S-14157 Huddinge, Sweden.
Jarvis, Rebecca (author)
Neurosci, BioPharmaceut R&D, AstraZeneca, Cambridge, England.
Bürli, Roland (author)
Neurosci, BioPharmaceut R&D, AstraZeneca, Cambridge, England.
Jamier, Tanguy (author)
Neurosci, BioPharmaceut R&D, AstraZeneca, Cambridge, England.
Franssen, Elske (author)
Neurosci, BioPharmaceut R&D, AstraZeneca, Cambridge, England.
Firth, Mike (author)
AstraZeneca, R&D, Data Sci & Quantitat Biol, Discovery Sci, Gothenburg, Sweden.
Degasperi, Andrea (author)
AstraZeneca, R&D, Data Sci & Quantitat Biol, Discovery Sci, Gothenburg, Sweden.;Univ Cambridge, Early Canc Inst, Cambridge, England.,University of Cambridge
Bendtsen, Claus (author)
AstraZeneca, R&D, Data Sci & Quantitat Biol, Discovery Sci, Gothenburg, Sweden.
Menzies, Robert I. (author)
Biosci Renal Res & Early Dev, Cardiovasc Renal & Metab CVRM, BioPharmaceut R&D, AstraZeneca, Gothenburg, Sweden.
Streckfuss-Bömeke, Katrin (author)
German Centre for Cardiovascular Research,Julius Maximilian University of Würzburg,University Hospital of Wϋrzburg,Univ Wurzburg, Inst Pharmacol & Toxicol, Wurzburg, Germany.;Georg August Univ Gottingen, Clin Cardiol & Pneumol, Gottingen, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Gottingen, Gottingen, Germany.;Univ Clin Wurzburg, Comprehens Heart Failure Ctr CHFC, Dept Translat Res, Wurzburg, Germany.
Kohlhaas, Michael (author)
University Hospital of Wϋrzburg,Univ Clin Wurzburg, Comprehens Heart Failure Ctr CHFC, Dept Translat Res, Wurzburg, Germany.
Nickel, Alexander G. (author)
University Hospital of Wϋrzburg,Univ Clin Wurzburg, Comprehens Heart Failure Ctr CHFC, Dept Translat Res, Wurzburg, Germany.
Lund, Lars H. (author)
Karolinska Institutet,Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden.
Maack, Christoph (author)
University Hospital of Wϋrzburg,Univ Clin Wurzburg, Comprehens Heart Failure Ctr CHFC, Dept Translat Res, Wurzburg, Germany.
Végvári, Ákos (author)
Karolinska Institutet,Karolinska Institute,Karolinska Inst, Dept Med Biochem & Biophys, Div Chem 1, Stockholm, Sweden.
Betsholtz, Christer (author)
Uppsala universitet,Uppsala University,Karolinska Institute,Vaskulärbiologi,Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, S-14157 Huddinge, Sweden
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 (creator_code:org_t)
Springer Nature, 2024
2024
English.
In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15
Related links:
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https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)
NATURVETENSKAP  -- Biologi -- Bioinformatik och systembiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Bioinformatics and Systems Biology (hsv//eng)
NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

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