Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response

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 () and Seung-Jae V. Lee ()
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Eunah Kim: Korea Advanced Institute of Science and Technology
Andrea Annibal: Max Planck Institute for Biology of Ageing
Yujin Lee: Korea Advanced Institute of Science and Technology
Hae-Eun H. Park: Korea Advanced Institute of Science and Technology
Seokjin Ham: Korea Advanced Institute of Science and Technology
Dae-Eun Jeong: Pohang University of Science and Technology
Younghun Kim: Korea Advanced Institute of Science and Technology
Sangsoon Park: Korea Advanced Institute of Science and Technology
Sujeong Kwon: Korea Advanced Institute of Science and Technology
Yoonji Jung: Korea Advanced Institute of Science and Technology
JiSoo Park: Korea Advanced Institute of Science and Technology
Sieun S. Kim: Korea Advanced Institute of Science and Technology
Adam Antebi: Max Planck Institute for Biology of Ageing
Seung-Jae V. Lee: Korea Advanced Institute of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39393-6

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