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

ElBeck, Zaher ; Hossain, Mohammad Bakhtiar ; Siga, Humam ; Oskolkov, Nikolay LU ; Karlsson, Fredrik ; Lindgren, Julia ; Walentinsson, Anna ; Koppenhöfer, Dominique ; Jarvis, Rebecca and Bürli, Roland , et al. (2024) In Nature Communications 15.
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
15
article number
2358
publisher
Nature Publishing Group
external identifiers
  • pmid:38509128
  • scopus:85188244415
ISSN
2041-1723
DOI
10.1038/s41467-024-46384-8
language
English
LU publication?
yes
id
059679b3-a3de-4420-b141-78330bc5b847
date added to LUP
2024-04-04 09:15:04
date last changed
2024-04-18 11:29:22
@article{059679b3-a3de-4420-b141-78330bc5b847,
  abstract     = {{<p>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.</p>}},
  author       = {{ElBeck, Zaher and Hossain, Mohammad Bakhtiar and Siga, Humam and Oskolkov, Nikolay and Karlsson, Fredrik and Lindgren, Julia and Walentinsson, Anna and Koppenhöfer, Dominique and Jarvis, Rebecca and Bürli, Roland and Jamier, Tanguy and Franssen, Elske and Firth, Mike and Degasperi, Andrea and Bendtsen, Claus and Menzies, Robert I. and Streckfuss-Bömeke, Katrin and Kohlhaas, Michael and Nickel, Alexander G. and Lund, Lars H. and Maack, Christoph and Végvári, Ákos and Betsholtz, Christer}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{03}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Epigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-46384-8}},
  doi          = {{10.1038/s41467-024-46384-8}},
  volume       = {{15}},
  year         = {{2024}},
}