Mitochondrial ROS

COVID-19

Monocytes/macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF1A) and consequently promotes glycolysis. HIF1A-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting mitochondrial ROS may have great therapeutic potential for the development of novel drugs to treat patients with coronavirus.

Aging

Mitochondrial ROS can promote cellular senescence and aging phenotypes in the skin of mice. Ordinarily mitochondrial SOD2 protects against mitochondrial ROS. Epidermal cells in mutant mice with a genetic SOD2 deficiency undergo cellular senescence, nuclear DNA damage, and irreversible arrest of proliferation in a portion of their keratinocytes.

Mutant mice with a conditional deficiency for mitochondrial SOD2 in connective tissue have an accelerated aging phenotype. This aging phenotype includes weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis, muscle degeneration and reduced life span.

DNA damage

Mitochondrial ROS attack DNA readily, generating a variety of DNA damages such as oxidized bases and strand breaks. The major mechanism that cells use to repair oxidized bases such as 8-hydroxyguanine, formamidopyrimidine and 5-hydroxyuracil is base excision repair (BER). BER occurs in both the cell nucleus and in mitochondria.

References

References

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2. (October 30, 2018). "Mitochondrial complex IV mutation increases ROS production and reduces lifespan in aged mice.". Acta Physiologica.
3. (March 2017). "Mitochondrial ROS, uncoupled from ATP synthesis, determine endothelial activation for both physiological recruitment of patrolling cells and pathological recruitment of inflammatory cells.". Can J Physiol Pharmacol.
4. (2019-03-19). "Mitochondrial ROS generated at the complex-II matrix or intermembrane space microdomain have distinct effects on redox signaling and stress sensitivity in C. elegans.". Antioxidants & Redox Signaling.
5. (November 2018). "Acute HIIE elicits similar changes in human skeletal muscle mitochondrial H 2 O 2 release, respiration, and cell signaling as endurance exercise even with less work". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology.
6. (2015-01-02). "Sites of Superoxide and Hydrogen Peroxide Production by Muscle Mitochondria Assessed ex Vivo under Conditions Mimicking Rest and Exercise". Journal of Biological Chemistry.
7. (April 2016). "Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation". Arteriosclerosis, Thrombosis, and Vascular Biology.
8. (April 2011). "TLR signalling augments macrophage bactericidal activity through mitochondrial ROS.". Nature.
9. Finkel T. (February 2012). "Signal transduction by mitochondrial oxidants". J Biol Chem.
10. Cavounidis A, Mann EH. (June 2020). "SARS-CoV-2 has a sweet tooth". Nature Reviews Immunology.
11. (January 2012). "Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin". Aging (Albany NY).
12. (August 2015). "Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells". Proc. Natl. Acad. Sci. U.S.A..
13. (April 2011). "Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue". Aging Cell.
14. (January 2009). "Base excision repair of oxidative DNA damage and association with cancer and aging". Carcinogenesis.