Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response
Abstract Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown, in particular at the organism level. Here we show that mitochondrial aconitase, ACO-2, a Krebs cycle enzyme that catalyze...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39393-6 |
| _version_ | 1827916784294952960 |
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| author | Eunah Kim Andrea Annibal Yujin Lee Hae-Eun H. Park Seokjin Ham Dae-Eun Jeong Younghun Kim Sangsoon Park Sujeong Kwon Yoonji Jung JiSoo Park Sieun S. Kim Adam Antebi Seung-Jae V. Lee |
| author_facet | Eunah Kim Andrea Annibal Yujin Lee Hae-Eun H. Park Seokjin Ham Dae-Eun Jeong Younghun Kim Sangsoon Park Sujeong Kwon Yoonji Jung JiSoo Park Sieun S. Kim Adam Antebi Seung-Jae V. Lee |
| author_sort | Eunah Kim |
| collection | DOAJ |
| description | Abstract Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown, in particular at the organism level. Here we show that mitochondrial aconitase, ACO-2, a Krebs cycle enzyme that catalyzes the conversion of citrate to isocitrate, inhibits immunity against pathogenic bacteria in C. elegans. We find that the genetic inhibition of aco-2 decreases the level of oxaloacetate. This increases the mitochondrial unfolded protein response, subsequently upregulating the transcription factor ATFS-1, which contributes to enhanced immunity against pathogenic bacteria. We show that the genetic inhibition of mammalian ACO2 increases immunity against pathogenic bacteria by modulating the mitochondrial unfolded protein response and oxaloacetate levels in cultured cells. Because mitochondrial aconitase is highly conserved across phyla, a therapeutic strategy targeting ACO2 may eventually help properly control immunity in humans. |
| first_indexed | 2024-03-13T03:20:11Z |
| format | Article |
| id | doaj.art-76ceadb6d9c14ef9a0dd85f7da8d2b66 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T03:20:11Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-76ceadb6d9c14ef9a0dd85f7da8d2b662023-06-25T11:22:31ZengNature PortfolioNature Communications2041-17232023-06-0114111610.1038/s41467-023-39393-6Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein responseEunah Kim0Andrea Annibal1Yujin Lee2Hae-Eun H. Park3Seokjin Ham4Dae-Eun Jeong5Younghun Kim6Sangsoon Park7Sujeong Kwon8Yoonji Jung9JiSoo Park10Sieun S. Kim11Adam Antebi12Seung-Jae V. Lee13Department of Biological Sciences, Korea Advanced Institute of Science and TechnologyMax Planck Institute for Biology of AgeingDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Life Sciences, Pohang University of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyMax Planck Institute for Biology of AgeingDepartment of Biological Sciences, Korea Advanced Institute of Science and TechnologyAbstract Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown, in particular at the organism level. Here we show that mitochondrial aconitase, ACO-2, a Krebs cycle enzyme that catalyzes the conversion of citrate to isocitrate, inhibits immunity against pathogenic bacteria in C. elegans. We find that the genetic inhibition of aco-2 decreases the level of oxaloacetate. This increases the mitochondrial unfolded protein response, subsequently upregulating the transcription factor ATFS-1, which contributes to enhanced immunity against pathogenic bacteria. We show that the genetic inhibition of mammalian ACO2 increases immunity against pathogenic bacteria by modulating the mitochondrial unfolded protein response and oxaloacetate levels in cultured cells. Because mitochondrial aconitase is highly conserved across phyla, a therapeutic strategy targeting ACO2 may eventually help properly control immunity in humans.https://doi.org/10.1038/s41467-023-39393-6 |
| spellingShingle | Eunah Kim Andrea Annibal Yujin Lee Hae-Eun H. Park Seokjin Ham Dae-Eun Jeong Younghun Kim Sangsoon Park Sujeong Kwon Yoonji Jung JiSoo Park Sieun S. Kim Adam Antebi Seung-Jae V. Lee Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response Nature Communications |
| title | Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response |
| title_full | Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response |
| title_fullStr | Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response |
| title_full_unstemmed | Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response |
| title_short | Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response |
| title_sort | mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response |
| url | https://doi.org/10.1038/s41467-023-39393-6 |
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