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

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 and Christer Betsholtz
Additional contact information
Zaher ElBeck: Karolinska Institutet, Campus Flemingsberg
Mohammad Bakhtiar Hossain: AstraZeneca
Humam Siga: Karolinska Institutet, Campus Flemingsberg
Nikolay Oskolkov: National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Lund University
Fredrik Karlsson: Discovery Sciences, R&D, AstraZeneca
Julia Lindgren: AstraZeneca
Anna Walentinsson: AstraZeneca
Dominique Koppenhöfer: Karolinska Institutet, Campus Flemingsberg
Rebecca Jarvis: AstraZeneca
Roland Bürli: AstraZeneca
Tanguy Jamier: AstraZeneca
Elske Franssen: AstraZeneca
Mike Firth: Discovery Sciences, R&D, AstraZeneca
Andrea Degasperi: Discovery Sciences, R&D, AstraZeneca
Claus Bendtsen: Discovery Sciences, R&D, AstraZeneca
Robert I. Menzies: AstraZeneca
Katrin Streckfuss-Bömeke: University of Würzburg
Michael Kohlhaas: Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg
Alexander G. Nickel: Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg
Lars H. Lund: Karolinska University Hospital
Christoph Maack: Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg
Ákos Végvári: Karolinska Institutet
Christer Betsholtz: Karolinska Institutet, Campus Flemingsberg

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46384-8

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