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

Philip V Seegren; Taylor K Downs; Marta E Stremska; Logan R Harper; Ruofan Cao; Rachel J Olson; Clint M Upchurch; Catherine A Doyle; Joel Kennedy; Eric L Stipes; Norbert Leitinger; Ammasi Periasamy; Bimal N Desai

doi:10.1016/j.celrep.2020.108411

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

Cell Rep. 2020 Nov 24;33(8):108411. doi: 10.1016/j.celrep.2020.108411.

Affiliations

¹ 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.
² 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.
³ Pharmacology Department, University of Virginia, Pinn Hall, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
⁴ The W.M. Keck Center for Cellular Imaging, University of Virginia, Physical and Life Sciences Building (PLSB), 90 Geldard Drive, Charlottesville, VA 22904, USA; Departments of Biology, University of Virginia, Physical and Life Sciences Building (PLSB), 90 Geldard Drive, Charlottesville, VA 22904, USA.
⁵ 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. Electronic address: bdesai@virginia.edu.

Abstract

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.

Keywords: MCU; NADPH; calcium; citrate; electrometabolic; immunometabolism; mitochondria, Ca(2+); phagosome; pyruvate dehydrogenase.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Calcium / metabolism*
Candida albicans / pathogenicity*
Mice
Mitochondria / metabolism*
Phagosomes / metabolism*
Signal Transduction

Substances

Calcium