Cycling on with Decreased Mitochondrial Function

Science Signaling  26 Feb 2008:
Vol. 1, Issue 8, pp. ec73
DOI: 10.1126/stke.18ec73

Erythropoiesis depends on the coordinated proliferation and differentiation of erythroid precursors into mature erythrocytes; thus, erythrocyte maturation is tied to regulation of the cell cycle. Sankaran et al. used mice that specifically lacked Rb (retinoblastoma protein) in cells of the erythroid lineage (pRbΔ/Δ mice) to investigate the controversial role of this cell cycle regulator in erythropoiesis. The pRbΔ/Δ mice exhibited a moderate anemia associated with an increase in circulating erythropoietin; analysis of red blood cell life span and of hematopoiesis in bone marrow and spleen indicated that loss of Rb was associated with the ineffective maturation of early erythroblasts to late erythroblasts. Transplantation experiments suggested that these effects of Rb were not only intrinsic to erythroid lineage cells but also cell autonomous. Gene expression profiling of early erythroblasts revealed up-regulation of various S-phase genes that are typically repressed during exit from the cell cycle; additionally--and unexpectedly--the expression of genes encoding components of the mitochondrial electron transport and oxidative phosphorylation pathways was decreased. Moreover, early erythroblasts from the bone marrow of pRbΔ/Δ mice showed a decrease in both functional mitochondria and mitochondrial DNA. Expression of the transcriptional coactivator PGC-1β (which has been implicated in mitochondrial biogenesis) was decreased, and both pharmacological inhibition of mitochondrial biogenesis and siRNA directed against PGC-1β inhibited erythroid differentiation in a cell culture model of late-stage erythropoiesis. The authors present a model for how exit from the cell cycle could be linked to mitochondrial biogenesis to promote erythrocyte differentiation and, noting the similarities between erythropoiesis in pRbΔ/Δ mice and that in human myelodysplastic syndrome, propose that these findings may have therapeutic implications.

V. G. Sankaran, S. H. Orkin, C. R. Walkley, Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis. Genes & Dev. 22, 463-475 (2008). [Abstract] [Full Text]