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Mitochondrial Ca(2+) 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 Ca(2+) relay to meet the bioenergetic demands of...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793167/ https://www.ncbi.nlm.nih.gov/pubmed/33238121 http://dx.doi.org/10.1016/j.celrep.2020.108411 |
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author | 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. |
author_facet | 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. |
author_sort | Seegren, Philip V. |
collection | PubMed |
description | 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 Ca(2+) relay to meet the bioenergetic demands of phagosomal killing. Upon detection of a fungal pathogen, macrophages rapidly elevate cytosolic Ca(2+) (phase 1), and by concurrently activating the mitochondrial Ca(2+) (mCa(2+)) uniporter (MCU), they trigger a rapid influx of Ca(2+) into the mitochondria (phase 2). mCa(2+) signaling reprograms mitochondrial metabolism, at least in part, through the activation of pyruvate dehydrogenase (PDH). Deprived of mCa(2+) 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 Ca(2+) signaling is an electrometabolic switch to fuel phagosome killing. |
format | Online Article Text |
id | pubmed-7793167 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-77931672021-01-08 Mitochondrial Ca(2+) 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. Cell Rep Article 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 Ca(2+) relay to meet the bioenergetic demands of phagosomal killing. Upon detection of a fungal pathogen, macrophages rapidly elevate cytosolic Ca(2+) (phase 1), and by concurrently activating the mitochondrial Ca(2+) (mCa(2+)) uniporter (MCU), they trigger a rapid influx of Ca(2+) into the mitochondria (phase 2). mCa(2+) signaling reprograms mitochondrial metabolism, at least in part, through the activation of pyruvate dehydrogenase (PDH). Deprived of mCa(2+) 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 Ca(2+) signaling is an electrometabolic switch to fuel phagosome killing. 2020-11-24 /pmc/articles/PMC7793167/ /pubmed/33238121 http://dx.doi.org/10.1016/j.celrep.2020.108411 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article 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. Mitochondrial Ca(2+) Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing |
title | Mitochondrial Ca(2+) Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing |
title_full | Mitochondrial Ca(2+) Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing |
title_fullStr | Mitochondrial Ca(2+) Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing |
title_full_unstemmed | Mitochondrial Ca(2+) Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing |
title_short | Mitochondrial Ca(2+) Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing |
title_sort | mitochondrial ca(2+) signaling is an electrometabolic switch to fuel phagosome killing |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793167/ https://www.ncbi.nlm.nih.gov/pubmed/33238121 http://dx.doi.org/10.1016/j.celrep.2020.108411 |
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