Division of Molecular Immunology, Universitätsklinikum Erlangen, Nikolaus-Fiebiger-Zentrum, FAU Erlangen-Nürnberg, Erlangen, Germany.
MitoVasc, University of Angers, UMR CNRS 6015/INSERM U1083, Angers, France.
Cell Rep. 2022 Jun 7;39(10):110912. doi: 10.1016/j.celrep.2022.110912.
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 HIF1α is stabilized. Hence, mitochondrial DNA controls the metabolism of activated B cells via OxPhos to foster humoral immunity.
为了阐明氧化磷酸化（OxPhos）在 B 细胞分化过程中的作用，我们利用 CD23Cre 驱动的线粒体解旋酶 Twinkle（DNT）的显性负 K320E 突变体的表达。DNT 表达在 B 细胞成熟过程中消耗线粒体 DNA，减少线粒体 DNA 编码的呼吸链蛋白亚基的丰度，从而导致活化 B 细胞中的呼吸链超级复合物减少。尽管 DNT 小鼠中的 B 细胞发育正常，但 B 细胞增殖、生发中心、IgG 类别转换、浆细胞成熟以及 T 细胞依赖性和非依赖性体液免疫均减弱。DNT 表达抑制 OxPhos，但增加脂多糖和 B 细胞受体激活细胞中的糖酵解。脂多糖激活的 DNT-B 细胞表现出糖酵解、戊糖磷酸途径和三羧酸循环的代谢物改变，以及更少的磷脂酸。因此，mTORC1 活性和 BLIMP1 诱导受到抑制，而 HIF1α 被稳定。因此，线粒体 DNA 通过 OxPhos 控制活化 B 细胞的代谢，以促进体液免疫。
