Editors' ChoiceCell Biology

New connections: mTORC1 matures red blood cells

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Sci. Signal.  27 Jun 2017:
Vol. 10, Issue 485, eaao1219
DOI: 10.1126/scisignal.aao1219

Erythrocytes need mTORC1 for mitochondrial biogenesis and hemoglobin production.

As hematopoietic stem/progenitor cells mature into red blood cells (erythrocytes), changes in metabolism, gene expression, and protein translation occur that enable these cells to transport oxygen bound to the protein complex hemoglobin. Two papers identify the protein complex mTORC1, which couples protein translation to nutrient availability, as a critical factor for the differentiation and function of erythrocytes. Liu et al. found that mTORC1 signaling was increased during erythropoiesis, which promoted the translation of mRNAs encoding mitochondria-associated proteins. These included the transcription factor TFAM, which mediates transcription and replication of the mitochondrial genome, and PHB2, which acts as a scaffolding protein in the mitochondria. Loss of PHB2 or TFAM in pro-erythrocytes reduced mitochondrial DNA content and mitochondrial mass, which was associated with decreased differentiation, proliferation, and survival. Mice with an erythroid-specific deficiency in Tfam were anemic and showed decreases in mitochondrial mass and erythroid differentiation. The authors speculate that mitochondrial biogenesis in response to mTORC1 activation during erythroid differentiation is necessary to produce the ATP needed to fuel hemoglobin production. The globin chains that constitute hemoglobin have a particularly high percentage of leucine residues. Because leucine activates mTORC1, Chung et al. investigated the role of mTORC1 in hemoglobin production. Deficiency or inhibition of LAT3, an uptake transporter for L-leucine, prevented hemoglobin production in zebrafish and mouse red blood cells. Inadequate L-leucine uptake prevented the translation of globin-encoding transcripts, demonstrating that leucine availability is coupled to hemoglobin production and erythrocyte function. Collectively, these results may explain why the clinical use of mTORC1 inhibitors is associated with the development of anemia.

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