Pharmacology Department, University of Virginia, Pinn Hall, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA; Carter Immunology Center, University of Virginia, 345 Crispell r. MR-6, Charlottesville, VA 22908, USA.
Carter Immunology Center, University of Virginia, 345 Crispell r. MR-6, Charlottesville, VA 22908, USA; Microbiology, Immunology, and Cancer Biology Department, University of Virginia, Pinn Hall, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
Cell Rep. 2020 Nov 24;33(8):108411. doi: 10.1016/j.celrep.2020.108411.
Phagocytes reallocate metabolic resources to kill engulfed pathogens, but the intracellular signals that rapidly switch the immunometabolic program necessary to fuel microbial killing are not understood. We report that macrophages use a fast two-step Ca relay to meet the bioenergetic demands of phagosomal killing. Upon detection of a fungal pathogen, macrophages rapidly elevate cytosolic Ca (phase 1), and by concurrently activating the mitochondrial Ca (mCa) uniporter (MCU), they trigger a rapid influx of Ca into the mitochondria (phase 2). mCa signaling reprograms mitochondrial metabolism, at least in part, through the activation of pyruvate dehydrogenase (PDH). Deprived of mCa signaling, Mcu macrophages are deficient in phagosomal reactive oxygen species (ROS) production and defective at killing fungi. Mice lacking MCU in their myeloid cells are highly susceptible to disseminated candidiasis. In essence, this study reveals an elegant design principle that MCU-dependent Ca signaling is an electrometabolic switch to fuel phagosome killing.
吞噬细胞重新分配代谢资源以杀死吞噬的病原体，但尚不清楚快速切换免疫代谢程序以提供微生物杀伤所需的细胞内信号。我们报告称，巨噬细胞使用快速的两步 Ca 级联反应来满足吞噬体杀伤的生物能量需求。在检测到真菌病原体后，巨噬细胞迅速升高细胞质 Ca（第 1 阶段），并通过同时激活线粒体 Ca（mCa）单向转运蛋白（MCU），它们触发 Ca 快速流入线粒体（第 2 阶段）。mCa 信号通过激活丙酮酸脱氢酶（PDH）至少部分地重新编程线粒体代谢。缺乏 mCa 信号的 Mcu 巨噬细胞在吞噬体活性氧（ROS）产生方面存在缺陷，并且在杀死真菌方面存在缺陷。其髓样细胞中缺乏 MCU 的小鼠对播散性念珠菌病高度敏感。从本质上讲，这项研究揭示了一个优雅的设计原则，即依赖 MCU 的 Ca 信号是为吞噬体杀伤提供动力的电代谢开关。
