Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells

Urbanczyk, S.; Baris, O.; Hofmann, J.; Golombek, F.; Castiglione, K.; Meng, X.; Bozec, A.; Mougiakakos, D.; Schulz, S. R.; Schuh, W.; Schloetzer-Schrehardt, U.; Steinmetz, T.; Brodesser, S.; Wiesner, R. J.; Mielenz, D.

doi:10.1101/2021.01.14.426649

bioRxiv · 10.1101/2021.01.14.426649

Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells

Urbanczyk, S.·Baris, O.·Hofmann, J.·Golombek, F.·Castiglione, K.·Meng, X.·Bozec, A.·Mougiakakos, D.·Schulz, S. R.·Schuh, W.·Schloetzer-Schrehardt, U.·Steinmetz, T.·Brodesser, S.·Wiesner, R. J.·Mielenz, D.

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Abstract

The function of mitochondrial respiration during B cell fate decisions and differentiation remains equivocal. This study reveals that selection for mitochondrial fitness occurs during B cell activation and is essential for subsequent plasma cell differentiation. By expressing a mutated mitochondrial helicase in transitional B cells, we depleted mitochondrial DNA during B cell maturation, resulting in reduced oxidative phosphorylation. Although no changes in follicular B cell development were evident, germinal centers, class switch recombination to IgG, plasma cell generation and humoral immunity were diminished. Defective oxidative phosphorylation led to aberrant flux of the tricarboxylic acid cycle and lowered the amount of saturated phosphatidic acid. Consequently, MTOR activity and BLIMP-1 induction were curtailed whereas HIF1, glycolysis and AMPK activity were amplified. Exogenous phosphatidic acid increased mTOR activity in activated B cells. Hence, mitochondrial function is required and selected for in activated B cells for the successful generation of functional plasma cells.

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Urbanczyk, S., Baris, O., Hofmann, J., Golombek, F., Castiglione, K., Meng, X., Bozec, A., Mougiakakos, D., Schulz, S. R., Schuh, W., Schloetzer-Schrehardt, U., Steinmetz, T., Brodesser, S., Wiesner, R. J., Mielenz, D.. 2021-01-16. Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells. https://doi.org/10.1101/2021.01.14.426649

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