Journal
CELL REPORTS
Volume 39, Issue 10, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.110912
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [TRR130, 1660]
- Deutsche Forschungsgemeinschaft [SFB 829/A14]
- Deutsche Forschungsgemeinschaft (Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases - CECAD)
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The metabolism of activated B cells is regulated by mitochondrial DNA and oxidative phosphorylation (OxPhos), which plays a crucial role in promoting humoral immunity.
To elucidate the function of oxidative phosphorylation (OxPhos) during B cell differentiation, we employ CD23Cre-driven expression of the dominant-negative K320E mutant of the mitochondrial helicase Twinkle (DNT). DNT-expression depletes mitochondrial DNA during B cell maturation, reduces the abundance of respiratory chain protein subunits encoded by mitochondrial DNA, and, consequently, respiratory chain super complexes in activated B cells. Whereas B cell development in DNT mice is normal, B cell proliferation, germinal centers, class switch to IgG, plasma cell maturation, and T cell-dependent as well as T cell -independent humoral immunity are diminished. DNT expression dampens OxPhos but increases glycolysis in lipopolysaccharide and B cell receptor-activated cells. Lipopolysaccharide-activated DNT-B cells exhibit altered metabolites of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle and a lower amount of phosphatidic acid. Consequently, mTORC1 activity and BLIMP1 induction are curtailed, whereas HIF1a is stabilized. Hence, mitochondrial DNA controls the metabolism of activated B cells via OxPhos to foster humoral immunity.
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