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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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.
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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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