Zaher El Beck
Affiliated to research
My interest is in redox biology in the cardiovascular system, but from a different perspective than the way it has been commonly viewed.
Oxidative species are a divergent group of cellular metabolites, with a wide variety of functions. Together with reductants, they regulate almost all cellular functions, from mediating cellular communications, to catalyzing a variety of biochemical reactions, and post-translationally modifying proteins.
We demonstrate that in cardiomyocytes mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidant defense mechanism. In both male and female mice and humans, the paradoxical reduction in expression of IDH2 associated with heart failure is compensated for by an increase in the enzyme’s activity. We describe extensive mutual regulation of the antioxidant activities of IDH2 and NRF2 by a network involving 2-oxoglutarate and L2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. We highlight a sex difference in cardiac antioxidative capacity, which even influences cardiomyocyte morphology. Conditional targeting of ROS in a murine model of heart failure improves cardiac function in sex- and phenotype-dependent manners. To read more about my research, please see our recent manuscript (Epigenetic modulators link mitochondrial redox homeostasis to cardiac function) in BioRxiv (https://doi.org/10.1101/2022.03.26.485908).