Regulation of Energy Metabolism during Early B Lymphocyte Development

Abstract

The most important feature of humoral immunity is the adaptation of the diversity of newly generated B cell receptors, that is, the antigen receptor repertoire, to the body’s own and foreign structures. This includes the transient propagation of B progenitor cells and B cells, which possess receptors that are positively selected via anabolic signalling pathways under highly competitive conditions. The metabolic regulation of early B-cell development thus has important consequences for the expansion of normal or malignant pre-B cell clones. In addition, cellular senescence programs based on the expression of B cell identity factors, such as Pax5, act to prevent excessive proliferation and cellular deviation. Here, we review the basic mechanisms underlying the regulation of glycolysis and oxidative phosphorylation during early B cell development in bone marrow. We focus on the regulation of glycolysis and mitochondrial oxidative phosphorylation at the transition from non-transformed pro- to pre-B cells and discuss some ongoing issues. We introduce Swiprosin-2/EFhd1 as a potential regulator of glycolysis in pro-B cells that has also been linked to Ca2+-mediated mitoflashes. Mitoflashes are bioenergetic mitochondrial events that control mitochondrial metabolism and signalling in both healthy and disease states. We discuss how Ca2+ fluctuations in pro- and pre-B cells may translate into mitoflashes in early B cells and speculate about the consequences of these changes.

c-Myb expression is critical to maintain proliferation and glucose metabolism of large pre-B cells

“…The successive differentiation steps from pro-B to large pre-B to small pre-B cells involves changes in proliferative and metabolic status, in particular changes in their reliance on glucose uptake and metabolism (4,5). Pro-B cells maintain homeostatic levels of proliferation and metabolism while alternating between dividing populations engaged with IL-7-producing stromal cells and non-dividing populations that carry out V(D)J rearrangement at the IgH locus (2,6,7).…”

“…The copyright holder for this preprint this version posted September 10, 2020. ; https://doi.org/10.1101/2020.09.09.290346 doi: bioRxiv preprint glycolysis (5). Subsequently, with expression of the pre-BCR, large pre-B cells undergo a limited burst of proliferation fueled by increased glucose uptake and increased overall metabolic activity.…”

“…Subsequently, with expression of the pre-BCR, large pre-B cells undergo a limited burst of proliferation fueled by increased glucose uptake and increased overall metabolic activity. Similar to other highly proliferative cell types, large pre-B cells shift the majority of glucose utilization to glycolysis and the production of macromolecules to facilitate increased proliferation (5,8). Then, after a limited number of cell divisions, large pre-B cells exit the cell cycle and repress glucose metabolism in preparation for differentiation into quiescent small pre-B cells.…”

Isolating a reverse-mode ATP synthase–dependent mechanism of mitoflash activation

“…Mitoflashes are transient bursts of reactive oxygen species (ROS) that occur stochastically and concomitantly with matrix alkalinization and depolarization of the mitochondrial inner membrane potential (Ψ m ). They are observed in single mitochondria and local mitochondrial networks across a wide range of cell types (Wang et al, 2008; Pouvreau, 2010; Wei et al, 2011; Hou et al, 2012; Cao et al, 2013; Shen et al, 2014; Zhang et al, 2015; Urbanczyk et al, 2018). Mitoflashes were first described in cardiac myocytes using a mitochondrially targeted circularly permuted YFP (mt-cpYFP; Wang et al, 2008).…”

Cell Lineage Choice during Haematopoiesis: In Honour of Professor Antonius Rolink

“…By contrast, Urbanczyk and colleagues have shown that the cell surface expression of the pre-B cell receptor down-regulates EFhd1, a Ca2 + -binding protein that localises on the inner mitochondrial membrane and that limits glycolysis in pro-B cells. They therefore speculate on the importance of Ca2 + fluctuation-mediated mitochondrial flashes (mitoflashes) for the pro- to pre-B-cell transition [ 17 ].…”