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

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Hossain, Mohammad Bakhtiar  ORCID logo
Karlsson, Fredrik 


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.


Acknowledgements: We acknowledge all people who have contributed to this study, either by providing funds or technical assistance. We want to particularly acknowledge Mattias Svensson, Department of Medicine Huddinge, for his valuable intellectual input and feedback, Oscar Franzén for his valuable input in the epigenetic bioinformatic analysis, Cristobal Dos Remedios and Amy Li for the provision of the human heart samples from the Sydney biobank and for his scientific input to the manuscript. Byambajav Buyandelger for her valuable input and for helping in preparing samples for TEM. Anne-Laure Lainé, for preparing AZ925, David Brodin at the BEA facility, KI, Huddinge, for his support in analyzing the ShRNA-KD RNA seq data, Kjell Hultenby for performing the TEM and quantifying the images obtained, Sara Fernandez Leon and Charlotte Webster for their technical assistance, and Joseph W DePierre for scientific English editing of the manuscript. We would like to acknowledge the Single-cell core facility at the Flemingsberg campus (SICOF) at Karolinska Institutet (KI) for their sequencing. This facility is supported by grants from the KI Department of Medicine (MedH) and KI Infrastructure, as well as the infrastructure for the Strategic Research Area (SFO) on Stem Cells and Regenerative Medicine. Fluorescence microscopy was performed at the Live Cell Imaging Core facility/Nikon Center of Excellence at Karolinska Institutet, with support from the Swedish Research Council, KI infrastructure, and the Centre for Innovative Medicine. We also acknowledge Gisele Miranda for her input in the analysis of fluorescence images. The BioImage Informatics Facility for carrying out image analysis is funded by SciLifeLab, the National Microscopy Infrastructure, NMI (VR-RFI 2019-00217), and the Chan-Zuckerberg Initiative. The Proteomics Biomedicum core facility of Karolinska Institutet for performing the mass spectrometric analysis. Antibodies against VDAC, COX4I1, and NDUFB8 were a kind gift from Peter Rehling, Göttingen, and we thank Berkan Arslan for performing the Western blotting. We also acknowledge Hanna Ebrel from the Institute of Pharmacology and Toxicology, University of Würzburg, Germany, for her invaluable assistance in preparing and differentiating hiPSC-CMs. C.M. is supported by the German Research Foundation (DFG; SFB 894, TRR-219; Ma 2528/7-1) and the German Ministry of Education and Research (BMBF, 01EO1504). N.O. is supported financially by the Knut and Alice Wallenberg Foundation as part of the National Bioinformatics Infrastructure Sweden at SciLifeLab.


Mice, Animals, Reactive Oxygen Species, Oxidative Stress, Antioxidants, Oxidation-Reduction, Heart Failure, Cardiomegaly, Epigenesis, Genetic, Isocitrate Dehydrogenase

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