학술논문
Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Document Type
Author
ElBeck, Zaher; Hossain, Mohammad Bakhtiar; Siga, Humam; Oskolkov, Nikolay; Karlsson, Fredrik; Lindgren, Julia; Walentinsson, Anna; Koppenhöfer, Dominique; Jarvis, Rebecca; Bürli, Roland; Jamier, Tanguy; Franssen, Elske; Firth, Mike; Degasperi, Andrea; Bendtsen, Claus; Menzies, Robert I.; Streckfuss-Bömeke, Katrin; Kohlhaas, Michael; Nickel, Alexander G.; Lund, Lars H.; Maack, Christoph; Végvári, Ákos; Betsholtz, Christer
Source
Nature Communications. 15
Subject
Language
English
ISSN
2041-1723
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.