Description:
<jats:title>Abstract</jats:title>
<jats:p>Assessing metabolism during early B cell development we show here that large pre B cells are superior in their metabolic activity but small pre B cells down-regulate glycolysis significantly, both ex vivo and in IL-7 cultures. The mitochondrial Ca2+ binding protein Swiprosin-2/EFhd1 (EFhd1) has been proposed to balance mitochondrial Ca2+ and the mitochondrial membrane potential. We show here that EFhd1 is expressed in pro B cells but becomes downregulated by surface expression of the pre BCR. Conversely, EFhd1 becomes up-regulated again in plasma cells. A transgenic mouse model, where EFhd1 cannot be downregulated by the pre BCR anymore (EFhd1tg), revealed that the mitochondrial metabolic regulator PGC-1a is upregulated by EFhd1. This lead to mitochondrial dysfunction in EFhd1tg pre B cells, to a disadvantage for EFhd1tg pro and pre B cells in mixed bone marrow chimeras and to an increased mitochondrial proton leak in EFhd1tg LPS blasts. In accordance, EFhd1 transfected into 293 cells is enriched in the mitochondrial fraction and co-localizes with mitochondria. On the other hand, CRISPR-Cas9 mediated knock-out of EFhd1 in the pro B cell line 38B9 as a surrogate for the pre BCR signal increased glycolysis, glycolytic capacity and reserve, providing a mechanism for increased metabolic activity in large pre B cells. Thus, proper regulation of EFhd1 is important to equilibrate mitochondrial and glycolytic metabolism during B cell differentiation. To gain more insight into metabolic demands and mechanisms during B cell development, activation and differentiation we generated EFhd1KO mice. First experiments with EFhd1KO mice revealed an important function for EFhd1 during B cell development, differentiation and function.</jats:p>