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Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice
Mitochondrial function and innate immunity are intimately linked; however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. Herein we show that mitofusin-2 (MFN2), a mitochondrial fusion protein, promotes innate host defense through the maintena...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110749/ https://www.ncbi.nlm.nih.gov/pubmed/33972668 http://dx.doi.org/10.1038/s42003-021-02073-6 |
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author | Silwal, Prashanta Kim, Jin Kyung Jeon, Sang Min Lee, June-Young Kim, Young Jae Kim, Yi Sak Seo, Yeji Kim, Jihye Kim, Soo Yeon Lee, Min Joung Heo, Jun Young Jung, Mi-Ja Kim, Hyun Sik Hyun, Dong-Wook Han, Jeong Eun Whang, Jake Huh, Yang Hoon Lee, Sang-Hee Heo, Won Do Kim, Jin-Man Bae, Jin-Woo Jo, Eun-Kyeong |
author_facet | Silwal, Prashanta Kim, Jin Kyung Jeon, Sang Min Lee, June-Young Kim, Young Jae Kim, Yi Sak Seo, Yeji Kim, Jihye Kim, Soo Yeon Lee, Min Joung Heo, Jun Young Jung, Mi-Ja Kim, Hyun Sik Hyun, Dong-Wook Han, Jeong Eun Whang, Jake Huh, Yang Hoon Lee, Sang-Hee Heo, Won Do Kim, Jin-Man Bae, Jin-Woo Jo, Eun-Kyeong |
author_sort | Silwal, Prashanta |
collection | PubMed |
description | Mitochondrial function and innate immunity are intimately linked; however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. Herein we show that mitofusin-2 (MFN2), a mitochondrial fusion protein, promotes innate host defense through the maintenance of aerobic glycolysis and xenophagy via hypoxia-inducible factor (HIF)-1α during intracellular bacterial infection. Myeloid-specific MFN2 deficiency in mice impaired the antimicrobial and inflammatory responses against mycobacterial and listerial infection. Mechanistically, MFN2 was required for the enhancement of inflammatory signaling through optimal induction of aerobic glycolysis via HIF-1α, which is activated by mitochondrial respiratory chain complex I and reactive oxygen species, in macrophages. MFN2 did not impact mitophagy during infection; however, it promoted xenophagy activation through HIF-1α. In addition, MFN2 interacted with the late endosomal protein Rab7, to facilitate xenophagy during mycobacterial infection. Our findings reveal the mechanistic regulations by which MFN2 tailors the innate host defense through coordinated control of immunometabolism and xenophagy via HIF-1α during bacterial infection. |
format | Online Article Text |
id | pubmed-8110749 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81107492021-05-12 Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice Silwal, Prashanta Kim, Jin Kyung Jeon, Sang Min Lee, June-Young Kim, Young Jae Kim, Yi Sak Seo, Yeji Kim, Jihye Kim, Soo Yeon Lee, Min Joung Heo, Jun Young Jung, Mi-Ja Kim, Hyun Sik Hyun, Dong-Wook Han, Jeong Eun Whang, Jake Huh, Yang Hoon Lee, Sang-Hee Heo, Won Do Kim, Jin-Man Bae, Jin-Woo Jo, Eun-Kyeong Commun Biol Article Mitochondrial function and innate immunity are intimately linked; however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. Herein we show that mitofusin-2 (MFN2), a mitochondrial fusion protein, promotes innate host defense through the maintenance of aerobic glycolysis and xenophagy via hypoxia-inducible factor (HIF)-1α during intracellular bacterial infection. Myeloid-specific MFN2 deficiency in mice impaired the antimicrobial and inflammatory responses against mycobacterial and listerial infection. Mechanistically, MFN2 was required for the enhancement of inflammatory signaling through optimal induction of aerobic glycolysis via HIF-1α, which is activated by mitochondrial respiratory chain complex I and reactive oxygen species, in macrophages. MFN2 did not impact mitophagy during infection; however, it promoted xenophagy activation through HIF-1α. In addition, MFN2 interacted with the late endosomal protein Rab7, to facilitate xenophagy during mycobacterial infection. Our findings reveal the mechanistic regulations by which MFN2 tailors the innate host defense through coordinated control of immunometabolism and xenophagy via HIF-1α during bacterial infection. Nature Publishing Group UK 2021-05-10 /pmc/articles/PMC8110749/ /pubmed/33972668 http://dx.doi.org/10.1038/s42003-021-02073-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Silwal, Prashanta Kim, Jin Kyung Jeon, Sang Min Lee, June-Young Kim, Young Jae Kim, Yi Sak Seo, Yeji Kim, Jihye Kim, Soo Yeon Lee, Min Joung Heo, Jun Young Jung, Mi-Ja Kim, Hyun Sik Hyun, Dong-Wook Han, Jeong Eun Whang, Jake Huh, Yang Hoon Lee, Sang-Hee Heo, Won Do Kim, Jin-Man Bae, Jin-Woo Jo, Eun-Kyeong Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice |
title | Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice |
title_full | Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice |
title_fullStr | Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice |
title_full_unstemmed | Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice |
title_short | Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice |
title_sort | mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110749/ https://www.ncbi.nlm.nih.gov/pubmed/33972668 http://dx.doi.org/10.1038/s42003-021-02073-6 |
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