J Clin Invest. 2007 August 1; 117(8): 2075–2077.
doi: 10.1172/JCI32559.
Shilpa M. Hattangadi1,2 and Harvey F. Lodish1
1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. 2Children’s Hospital of Boston, Boston, Massachusetts, USA.
Red blood cell homeostasis is an excellent example of redox balance: erythroid progenitors accumulate hemoglobin during development, and erythrocytes continuously transport large amounts of oxygen over the course of their approximately 120-day lifespan. This results in a high level of oxidative stress (1). Fully mature red blood cells, lacking a nucleus, cannot produce new proteins in response to stress — they have to rely on proteins synthesized earlier in development to protect themselves from damage by ROS and thus ensure their own survival. Red blood cells have thus evolved to have an extensive array of antioxidants to counter this level of stress, including membrane oxidoreductases, cellular antioxidants such as catalase and superoxide dismutase (SOD), and enzymes that continuously produce reducing agents through the glutathione (GSH) system (2).
Defects in enzymes critical to the oxidative stress response have been implicated in human diseases ranging from mild chronic hemolysis to severe acute hemolysis (2). Because of a concomitant reduction in the normal red blood cell lifespan, these disease states are characterized by a compensatory increase in erythropoiesis, evident in patients as reticulocytosis. One relatively common genetic disorder is deficiency of glucose-6-phosphate dehydrogenase (G6PD), the enzyme that converts NADP to NADPH. NADPH is required for the maintenance of reduced GSH, and GSH in turn reduces peroxides, superoxides, and other ROS (2). G6PD is therefore required to protect the red blood cell from oxidative damage, and absence of this protection can result in severe hemolysis.
The deleterious effects of oxidative stress, such as damage to cellular proteins, DNA, and lipids, are well characterized. The dependence of the lifespan of the erythrocyte on an adequate antioxidant response has been previously demonstrated (3). However, the factors that regulate the oxidative stress response and the lifespan of erythrocytes are less clear.
Marinkovic et al. (10) suggest that the mitotic arrest observed in Foxo3-null Ter119+CD71+ erythrocyte precursors may be caused by p53-dependent G1-phase arrest induced as a response to stress through its downstream target, p21CIP1/WAF1/Sdi1, as both genes were upregulated in Foxo3-deficient erythroid precursors. There was also induction of the antioxidant p53 downstream targets GADD45 and sestrin 2 (SESN2). The authors speculate that the oxidative stress left unchecked by lack of Foxo3 likely turns on the p53 pathway in erythroid progenitors, resulting in induction of downstream targets that may mitigate oxidative stress and activate resistance to ROS-mediated damage.
Another interesting observation by Marinkovic et al. (10) was that the mitotic arrest and induction of p21CIP1/WAF1/Sdi1 in intermediate Foxo3-null erythroid progenitors was improved with NAC treatment. This raises the interesting possibility that ROS levels regulate Foxo3 or at least its function of initiating the oxidative stress response, creating a type of erythroid differentiation checkpoint. Hypothetically, when sufficient hemoglobin has been produced for the nascent terminal erythrocyte to carry out its oxygen-carrying tasks, the resulting oxidative stress from oxygen and heme moieties would somehow trigger Foxo3 translocation to the nucleus and induction of its targets in terminal differentiation. This as yet untested hypothesis emphasizes the importance of determining both the direct targets of Foxo3 and its own regulation in helping us understand how a red blood cell lacking a nucleus knows exactly when to die.
doi: 10.1172/JCI32559.
Shilpa M. Hattangadi1,2 and Harvey F. Lodish1
1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. 2Children’s Hospital of Boston, Boston, Massachusetts, USA.
Red blood cell homeostasis is an excellent example of redox balance: erythroid progenitors accumulate hemoglobin during development, and erythrocytes continuously transport large amounts of oxygen over the course of their approximately 120-day lifespan. This results in a high level of oxidative stress (1). Fully mature red blood cells, lacking a nucleus, cannot produce new proteins in response to stress — they have to rely on proteins synthesized earlier in development to protect themselves from damage by ROS and thus ensure their own survival. Red blood cells have thus evolved to have an extensive array of antioxidants to counter this level of stress, including membrane oxidoreductases, cellular antioxidants such as catalase and superoxide dismutase (SOD), and enzymes that continuously produce reducing agents through the glutathione (GSH) system (2).
Defects in enzymes critical to the oxidative stress response have been implicated in human diseases ranging from mild chronic hemolysis to severe acute hemolysis (2). Because of a concomitant reduction in the normal red blood cell lifespan, these disease states are characterized by a compensatory increase in erythropoiesis, evident in patients as reticulocytosis. One relatively common genetic disorder is deficiency of glucose-6-phosphate dehydrogenase (G6PD), the enzyme that converts NADP to NADPH. NADPH is required for the maintenance of reduced GSH, and GSH in turn reduces peroxides, superoxides, and other ROS (2). G6PD is therefore required to protect the red blood cell from oxidative damage, and absence of this protection can result in severe hemolysis.
The deleterious effects of oxidative stress, such as damage to cellular proteins, DNA, and lipids, are well characterized. The dependence of the lifespan of the erythrocyte on an adequate antioxidant response has been previously demonstrated (3). However, the factors that regulate the oxidative stress response and the lifespan of erythrocytes are less clear.
Marinkovic et al. (10) suggest that the mitotic arrest observed in Foxo3-null Ter119+CD71+ erythrocyte precursors may be caused by p53-dependent G1-phase arrest induced as a response to stress through its downstream target, p21CIP1/WAF1/Sdi1, as both genes were upregulated in Foxo3-deficient erythroid precursors. There was also induction of the antioxidant p53 downstream targets GADD45 and sestrin 2 (SESN2). The authors speculate that the oxidative stress left unchecked by lack of Foxo3 likely turns on the p53 pathway in erythroid progenitors, resulting in induction of downstream targets that may mitigate oxidative stress and activate resistance to ROS-mediated damage.
Another interesting observation by Marinkovic et al. (10) was that the mitotic arrest and induction of p21CIP1/WAF1/Sdi1 in intermediate Foxo3-null erythroid progenitors was improved with NAC treatment. This raises the interesting possibility that ROS levels regulate Foxo3 or at least its function of initiating the oxidative stress response, creating a type of erythroid differentiation checkpoint. Hypothetically, when sufficient hemoglobin has been produced for the nascent terminal erythrocyte to carry out its oxygen-carrying tasks, the resulting oxidative stress from oxygen and heme moieties would somehow trigger Foxo3 translocation to the nucleus and induction of its targets in terminal differentiation. This as yet untested hypothesis emphasizes the importance of determining both the direct targets of Foxo3 and its own regulation in helping us understand how a red blood cell lacking a nucleus knows exactly when to die.
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