Mitochondrial fatty acid utilization increases chromatin oxidative stress in cardiomyocytes
| Autor: | Nicholas T. Lam, Hesham A. Sadek, Salim Abdisalaam, Shibani Mukherjee, Aroumougame Asaithamby, Ivan Menendez-Montes, Feng Xiao, Luke I. Szweda |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
DNA damage
Heterochromatin Mitochondrion medicine.disease_cause Cell Line Mice medicine Animals Myocytes Cardiac Cell Proliferation reactive oxygen species chemistry.chemical_classification Reactive oxygen species Multidisciplinary Fatty Acids Cell Biology Biological Sciences Mitochondria Chromatin Cell biology Oxidative Stress chemistry Anaerobic glycolysis Nuclear lamina metabolism Oxidative stress DNA Damage |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2101674118 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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