Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner (Data set 1)

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. In this repository, we provide raw RNA sequencing data obtained from the left ventricle (LV) myocardium of male and female Mlp-/- animals as well as their littermate controls. Additionally, the repository contains raw RNA sequencing data from the LV of male and female Mlp-/- mice treated with the Nrf2 activator (AZ925), along with their respective scrambled controls. The study is published in Nature Communications DOI (https://doi.org/10.1038/s41467-024-46384-8).