Abstract
The Role of Mitochondrial Metabolism and Redox Signaling in Iron Deficiency Anemia
Blood, Vol.126(23), pp.2145-2145
12/03/2015
DOI: 10.1182/blood.V126.23.2145.2145
Abstract
Abstract
Several clinical observations illustrate the link between iron and erythropoietin (EPO)-mediated signaling in committed erythroid progenitor cells. In iron deficiency anemia (IDA), erythropoiesis is blocked despite increased serum EPO concentrations. Intravenous iron improves the effectiveness of exogenous EPO in patients with EPO-refractory anemia of chronic disease. These clinical observations suggest that iron dominantly regulates EPO-receptor signaling. However, the mechanism of this iron-mediated signaling remains unclear. We recently demonstrated that 1) the aconitases, multifunctional iron-sulfur cluster proteins that convert citrate into isocitrate are essential in the iron- EPO-signaling pathway in erythroid progenitor cells, and that 2) isocitrate, the product of aconitase, can enhance the effectiveness of EPO during iron deficiency in vitro and in mice with IDA and in rats with the anemia of chronic inflammation. These observations suggest that isocitrate, or its derivatives that synergize with erythropoiesis stimulating agents, have important therapeutic application in the treatment of anemia. New data shows that cellular iron restriction regulates mitochondrial oxygen consumption rates (OCR) differentially over time during erythropoiesis, suggesting a novel link between mitochondrial function and erythropoeisis. It is unknown how iron deficiency induced inhibition of mitochondrial aconitase (ACO2) regulates mitochondrial metabolism during RBC production. Pilot data show that ACO2 inhibition by cellular iron deprivation or pharmacological inhibition of ACO2 decreases mitochondrial respiratory rates (RRs) and alters reactive oxygen species (ROS) production. Further, isocitrate normalizes mitochondrial RRs and ROS and restores RBC production. Importantly, disruption of mitochondrial ROS generation with a mitochondrial-specific anti-oxidant blocks RBC production and a subset of oxidant generators promote erythropoiesis. Targeted reduction of ACO2 protein expression and enzyme activity in iron replete stably transduced K562 cells decreases OCRs. This confirms the link between ACO2 and mitochondrial metabolism in human erythroid cells. These data inform our overarching hypothesis that iron-restriction inhibits ACO2, thereby inhibiting mitochondrial metabolism, resulting in the loss of a mitochondrial ROS signal that is required for erythropoiesis. The loss of this critical mitochondrial ROS signal inhibits the EPO signaling that is required for RBC production. These data also suggest that ACO2 is an iron-sensing regulator of mitochondrial metabolism and ROS signaling.
Disclosures
No relevant conflicts of interest to declare.
Details
- Title: Subtitle
- The Role of Mitochondrial Metabolism and Redox Signaling in Iron Deficiency Anemia
- Creators
- Grant C Bullock - University of PittsburghChanté L Richardson - Alabama College of Osteopathic MedicineValerie Schrott - University of PittsburghNaomi D Gunawardena - University of PittsburghTeague Nolan Cole - University of PittsburghCatherine G Corey - University of PittsburghSruti S Shiva - University of Pittsburgh
- Resource Type
- Abstract
- Publication Details
- Blood, Vol.126(23), pp.2145-2145
- Publisher
- AMER SOC HEMATOLOGY; WASHINGTON
- DOI
- 10.1182/blood.V126.23.2145.2145
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Number of pages
- 1
- Language
- English
- Date published
- 12/03/2015
- Academic Unit
- Pathology
- Record Identifier
- 9984700254502771
Metrics
1 Record Views