Mitochondrial Ca²⁺ Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing.

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 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. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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