Cell reports · 2020
Mitochondrial Ca2+ Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Seegren Philip V, Downs Taylor K, Stremska Marta E, Harper Logan R, Cao Ruofan, Olson Rachel J, Upchurch Clint M, Doyle Catherine A, Kennedy Joel, Stipes Eric L, Leitinger Norbert, Periasamy Ammasi, Desai Bimal N
Аннотация
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 Ca2+ relay to meet the bioenergetic demands of phagosomal killing. Upon detection of a fungal pathogen, macrophages rapidly elevate cytosolic Ca2+ (phase 1), and by concurrently activating the mitochondrial Ca2+ (mCa2+) uniporter (MCU), they trigger a rapid influx of Ca2+ into the mitochondria (phase 2). mCa2+ signaling reprograms mitochondrial metabolism, at least in part, through the activation of pyruvate dehydrogenase (PDH). Deprived of mCa2+ 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 Ca2+ signaling is an electrometabolic switch to fuel phagosome killing.