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

• Published in: Cell reports (Cambridge) Vol. 33; no. 8; p. 108411
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 24.11.2020
• Subjects: calcium; citrate; electrometabolic; immunometabolism; MCU; mitochondria, Ca2; NADPH; phagosome; pyruvate dehydrogenase; NADPH; pyruvate dehydrogenase; mitochondria, Ca2; calcium; citrate; immunometabolism; phagosome; electrometabolic; MCU
• ISSN: 2211-1247; 2211-1247
• 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 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. [Display omitted] •Identification of MCU as a major regulator of phagosomal killing by macrophages•Mice lacking Mcu in myeloid cells are highly susceptible to in vivo candidiasis•Fungal pathogens elicit mCa2+ elevations using a fast two-phase Ca2+ relay•mCa2+ signaling activates pyruvate dehydrogenase during phagocytosis The signaling mechanisms that rapidly reallocate metabolic resources to meet the bioenergetic demands of microbial killing are not understood. Seegren et al. show that mitochondrial Ca2+ signaling serves as a fast electrometabolic switch to fuel microbial killing by phagocytes. This study identifies the mitochondrial Ca2+ channel MCU as a critical component of cell-intrinsic antimicrobial responses.