Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis

Abstract

Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor A, mitochondrial (TFAM). TFAM, while also necessary for normal B cell development, is required for entry of activated GC precursor B cells into the germinal center reaction; deletion of Tfam significantly impairs GC formation, function and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation and that deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacological inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells and induces similar defects in the actin cytoskeleton.

Plasma cell differentiation, antibody quality, and initial germinal center B cell population depend on glucose influx rate

“…Although the trend of data was that the fraction of GC B cells in S-phase was reduced (Fig 3D), the difference did not achieve statistical significance – which may in part relate to counter-selection and inclusion of B cells with non-deleted Slc2a1 in these GC (Fig 3E). Of note, however, the decrease in frequencies of BrdU + events was more significant for activated (IgD neg ) B cells that were GL7 neg – a population that has been treated as “activated precursors” or pre-GC blasts (38). This result shows that proliferation amongst some B cells in vivo is reduced by inactivation of Slc2a1 at the outset.…”

Asparagine availability controls B cell homeostasis

“…This was reflected in reduced MitoTracker signal and mitochondrial reactive oxygen species production, measured by flow cytometry (Extended Data Fig. 7D-E) B cells undergo profound mitochondrial remodelling upon activation associated with mitochondrial protein synthesis of electron transport chain (ETC) proteins 36 . Given the defective cytoplasmic protein translation we observed with Asn deprivation, we examined whether mitochondrial translation and ETC homeostasis was also affected.…”

Translatomics to explore dynamic differences in immunocytes in the tumor microenvironment

“…Inhibition of mitochondrial transcription and translation can inhibit the growth of human lymphoma. 118 Ribo-seq showed that the RNA-binding protein HuR (Elavl1) can also alter the translation of B cell mRNA, resulting in metabolic imbalances that impair its function. 119 In conclusion, the function and activation of B cells in the TME also change due to changes in the environment, and crosstalk will occur between immune cells coexisting in the microenvironment to regulate antitumor immunity.…”