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

Abstract

Germinal centre (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 mitochondrial A (TFAM). TFAM, whilst also necessary for normal B cell development, is required for entry of activated GC-precursor B cells into the germinal centre reaction, and 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 signalling, leading to their spatial disorganisation. We show that B cell lymphoma substantially increases mitochondrial translation, and deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic model. Finally, we show that pharmacologic inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells, and induces similar defects in the actin cytoskeleton.