A defined metabolic state in pre B cells governs B-cell development and is counterbalanced by Swiprosin-2/EFhd1

Cell Death Differ. 2017 Jul;24(7):1239-1252. doi: 10.1038/cdd.2017.52. Epub 2017 May 19.

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.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / metabolism*
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Calcium-Binding Proteins / metabolism*
  • Cell Line
  • Down-Regulation
  • Gene Knockdown Techniques
  • Genes, Mitochondrial
  • Metabolome
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Oxygen Consumption
  • Precursor Cells, B-Lymphoid / metabolism*
  • Receptors, Antigen, B-Cell / metabolism

Substances

  • Calcium-Binding Proteins
  • Receptors, Antigen, B-Cell
  • Adenosine Triphosphate