Regulation of erythrocyte lifespan: do reactive oxygen species set the clock?
Shilpa M. Hattangadi, Harvey F. Lodish
Shilpa M. Hattangadi, Harvey F. Lodish
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2075-2077. https://doi.org/10.1172/JCI32559.
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Commentary

Regulation of erythrocyte lifespan: do reactive oxygen species set the clock?

Abstract

The forkhead box O (Foxo) subfamily of transcription factors regulates expression of genes important for many cellular processes, ranging from initiation of cell cycle arrest and apoptosis to induction of DNA damage repair. Invertebrate Foxo orthologs such as DAF-16 also regulate longevity. Cellular responses inducing resistance to ROS are important for cellular survival and organism lifespan, but until recently, mammalian factors regulating resistance to oxidative stress have not been well characterized. Marinkovic and colleagues demonstrate in this issue of the JCI that Foxo3 is specifically required for induction of proteins that regulate the in vivo oxidative stress response in murine erythrocytes (see the related article beginning on page 2133). Their work offers the interesting hypothesis that in so doing, Foxo3 may regulate the lifespan of red blood cells, and underlies the importance of understanding the direct targets of this transcription factor and its regulation.

Authors

Shilpa M. Hattangadi, Harvey F. Lodish

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Figure 1

The effects of lack of Foxo3 on the erythrocyte lifespan.

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The effects of lack of Foxo3 on the erythrocyte lifespan. (A) Wild-type ...
(A) Wild-type red blood cell development, in which Foxo3 induces the expression of antioxidants such as catalase, GADD45, and MnSOD in the erythroid progenitor. The terminally differentiated erythrocyte then develops normally and survives as expected (a mean of approximately 120 days). (B) As reported by Marinkovic et al. (10) in this issue of the JCI, the lack of Foxo3 in erythroid progenitor cells of Foxo3-null mice results in an increase in ROS in the terminal red blood cell, which ultimately results in a reduction in red blood cell lifespan. These animals also had evidence of hemolytic anemia, including reticulocytosis and splenomegaly. This scenario is similar to that found in G6PD deficiency, in which lack of the enzyme that helps to convert NADP to NADPH results in hemolytic anemia and a shortened red blood cell lifespan. (C) Reversal of this detrimental effect on red blood cell lifespan by administration of exogenous antioxidant to the Foxo3-null animals, most likely due to the decrease in ROS.