Mitochondrial fatty acid utilization increases chromatin oxidative stress in cardiomyocytes

Ivan Menendez-Montes, Salim Abdisalaam, Feng Xiao, Nicholas T. Lam, Shibani Mukherjee, Luke I. Szweda, Aroumougame Asaithamby, Hesham A. Sadek

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The inability of adult mammalian cardiomyocytes to proliferate underpins the development of heart failure following myocardial injury. Although the newborn mammalian heart can spontaneously regenerate for a short period of time after birth, this ability is lost within the first week after birth in mice, partly due to increased mitochondrial reactive oxygen species (ROS) production which results in oxidative DNA damage and activation of DNA damage response. This increase in ROS levels coincides with a postnatal switch from anaerobic glycolysis to fatty acid (FA) oxidation by cardiac mitochondria. However, to date, a direct link between mitochondrial substrate utilization and oxidative DNA damage is lacking. Here, we generated ROS-sensitive fluorescent sensors targeted to different subnuclear compartments (chromatin, heterochromatin, telomeres, and nuclear lamin) in neonatal rat ventricular cardiomyocytes, which allowed us to determine the spatial localization of ROS in cardiomyocyte nuclei upon manipulation of mitochondrial respiration. Our results demonstrate that FA utilization by the mitochondria induces a significant increase in ROS detection at the chromatin level compared to other nuclear compartments. These results indicate that mitochondrial metabolic perturbations directly alter the nuclear redox status and that the chromatin appears to be particularly sensitive to the prooxidant effect of FA utilization by the mitochondria.

Original languageEnglish (US)
Article numbere2101674118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number34
DOIs
StatePublished - Aug 24 2021

Keywords

  • Metabolism
  • Mitochondria
  • Reactive oxygen species

ASJC Scopus subject areas

  • General

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