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Mitochondrial Ca2+ Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing.
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.
Afiliação
  • Seegren PV; 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.
  • Downs TK; 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.
  • Stremska ME; 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.
  • Harper LR; Pharmacology Department, University of Virginia, Pinn Hall, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
  • Cao R; 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, US
  • Olson RJ; Pharmacology Department, University of Virginia, Pinn Hall, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
  • Upchurch CM; 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.
  • Doyle CA; 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.
  • Kennedy J; Pharmacology Department, University of Virginia, Pinn Hall, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
  • Stipes EL; Pharmacology Department, University of Virginia, Pinn Hall, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
  • Leitinger N; 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.
  • Periasamy A; 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, US
  • Desai BN; 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.
Cell Rep ; 33(8): 108411, 2020 11 24.
Article em En | MEDLINE | ID: mdl-33238121
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fagossomos / Candida albicans / Cálcio / Mitocôndrias Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Fagossomos / Candida albicans / Cálcio / Mitocôndrias Idioma: En Ano de publicação: 2020 Tipo de documento: Article