EFhd2 regulates microtubule-dependent mitochondrial fitness at the B cell immune synapse

Immobilized antigen induces an immune synapse, which is supported by Swiprosin-1/EFhd2 (EFhd2) in B and T cells. Here, we find that EFhd2 regulates mitochondrial fitness in the B cell synapse. Whereas activated EFhd2-deficient (KO) B cells show higher mitochondrial mass than wildtype (WT) B cells, this potential advantage reverses on coated anti-IgM antibodies: activated WT B cells enhance basal and maximal respiration as well as proton leak, with large increments of mitochondrial spare capacity, but EFhd2KO B cells fail to do so. Actin destabilization, but much more so microtubule destabilization, impairs mitochondrial up-regulation in WT, but not in EFhd2KO B cells. Conversely, microtubule stabilization, and to a lesser extent actin stabilization, restore mitochondrial spare capacity in EFhd2KO B cells at the BCR synapse. EFhd2KO B cells fail to coordinate the microtubule organization center, mitochondria and IgM BCRs upon synapse formation. Hence, microtubule-dependent mitochondrial organization at the immune synapse coordinates mitochondrial fitness in B cells via EFhd2.