| Literature DB >> 28524857 |
Merle Stein1, Sebastian Dütting1, Dimitrios Mougiakakos2, Michael Bösl3, Kristin Fritsch1, Dorothea Reimer1, Sophia Urbanczyk1, Tobit Steinmetz1, Wolfgang Schuh1, Aline Bozec4, Thomas H Winkler5, Hans-Martin Jäck1, Dirk Mielenz1.
Abstract
B-cell development in the bone marrow comprises proliferative and resting phases in different niches. We asked whether B-cell metabolism relates to these changes. Compared to pro B and small pre B cells, large pre B cells revealed the highest glucose uptake and ROS but not mitochondrial mass, whereas small pre B cells exhibited the lowest mitochondrial membrane potential. Small pre B cells from Rag1-/-;33.C9 μ heavy chain knock-in mice revealed decreased glycolysis (ECAR) and mitochondrial spare capacity compared to pro B cells from Rag1-/- mice. We were interested in the step regulating this metabolic switch from pro to pre B cells and uncovered that Swiprosin-2/EFhd1, a Ca2+-binding protein of the inner mitochondrial membrane involved in Ca2+-induced mitoflashes, is expressed in pro B cells, but downregulated by surface pre B-cell receptor expression. Knockdown and knockout of EFhd1 in 38B9 pro B cells decreased the oxidative phosphorylation/glycolysis (OCR/ECAR) ratio by increasing glycolysis, glycolytic capacity and reserve. Prolonged expression of EFhd1 in EFhd1 transgenic mice beyond the pro B cell stage increased expression of the mitochondrial co-activator PGC-1α in primary pre B cells, but reduced mitochondrial ATP production at the pro to pre B cell transition in IL-7 cultures. Transgenic EFhd1 expression caused a B-cell intrinsic developmental disadvantage for pro and pre B cells. Hence, coordinated expression of EFhd1 in pro B cells and by the pre BCR regulates metabolic changes and pro/pre B-cell development.Entities:
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Year: 2017 PMID： 28524857 PMCID： PMC5520169 DOI： 10.1038/cdd.2017.52
Source DB: PubMed Journal: Cell Death Differ ISSN： 1350-9047 Impact factor: 15.828