Iron overload-induced oxidative stress in myelodysplastic syndromes and its cellular sequelae
Cecilia H Kim1, Heather A Leitch2
1Faculty of Science, Department of Chemistry, Princeton University, Princeton, NJ, USA.
Abstract:
The myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders. MDS patients often require red blood cell transfusions, resulting in iron overload (IOL). IOL increases production of reactive oxygen species (ROS), oxygen free radicals. We review and illustrate how IOL-induced ROS influence cellular activities relevant to MDS pathophysiology. ROS damage lipids, nucleic acids in mitochondrial and nuclear DNA, structural proteins, transcription factors and enzymes. Cellular consequences include decreased metabolism and tissue and organ dysfunction. In hematopoietic stem cells (HSC), consequences of ROS include decreased glycolysis, shifting the cell from anaerobic to aerobic metabolism and causing HSC to exit the quiescent state, leading to HSC exhaustion or senescence. ROS oxidizes DNA bases, resulting in accumulation of mutations. Membrane oxidation alters fluidity and permeability. In summary, evidence indicates that IOL-induced ROS alters cellular signaling pathways resulting in toxicity to organs and hematopoietic cells, in keeping with adverse clinical outcomes in MDS.
Insights
Iron overload in myelodysplastic syndromes (MDS) generates harmful reactive oxygen species (ROS). These ROS damage cells, impacting hematopoietic stem cells and leading to organ dysfunction and adverse outcomes in MDS patients.
Area of Science:
- Hematology
- Cellular Biology
- Oxidative Stress Research
Background:
- Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders.
- MDS patients frequently require red blood cell transfusions, leading to iron overload (IOL).
- IOL is a significant contributor to increased reactive oxygen species (ROS) production.
Purpose of the Study:
- To review and illustrate the influence of IOL-induced ROS on cellular activities relevant to MDS pathophysiology.
- To elucidate the cellular consequences of ROS damage in the context of MDS.
Main Methods:
- Literature review and conceptual illustration of ROS-mediated damage.
- Analysis of ROS effects on cellular metabolism, DNA integrity, and cell signaling pathways.
- Focus on the impact of ROS on hematopoietic stem cells (HSCs).
Main Results:
- ROS generated by IOL damage lipids, nucleic acids (DNA), proteins, transcription factors, and enzymes.
- Cellular consequences include impaired metabolism, organ dysfunction, and HSC exhaustion or senescence.
- ROS induces DNA mutations and alters cell membrane properties, affecting fluidity and permeability.
Conclusions:
- IOL-induced ROS significantly contributes to MDS pathophysiology by damaging hematopoietic stem cells and organs.
- Altered cellular signaling pathways due to ROS toxicity lead to adverse clinical outcomes in MDS patients.
- Understanding ROS mechanisms is crucial for managing IOL-related complications in MDS.
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