Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation

Jiawei Yan; Xin Zhang; Huiying Wang; Xinglong Jia; Ruohong Wang; Shuangyang Wu; Zheng-Jiang Zhu; Minjia Tan; Tiffany Horng

doi:10.1016/j.celrep.2024.114780

Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation

Cell Rep. 2024 Sep 25;43(10):114780. doi: 10.1016/j.celrep.2024.114780. Online ahead of print.

Authors

Jiawei Yan¹, Xin Zhang¹, Huiying Wang¹, Xinglong Jia², Ruohong Wang³, Shuangyang Wu⁴, Zheng-Jiang Zhu⁵, Minjia Tan², Tiffany Horng⁶

Affiliations

¹ School of Life Sciences and Technology, ShanghaiTech University, Shanghai 201210, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ University of Chinese Academy of Sciences, Beijing 100049, China; Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
⁴ Gregor Mendel Institute of Molecular Plant Biology, Austrian Academy of Sciences, Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
⁵ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Shanghai Key Laboratory of Aging Studies, Shanghai 201210, China.
⁶ School of Life Sciences and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: tsyhorng@shanghaitech.edu.cn.

PMID: 39325625
DOI: 10.1016/j.celrep.2024.114780

Abstract

Macrophage elaboration of inflammatory responses is dynamically regulated, shifting from acute induction to delayed suppression during the course of infection. Here, we show that such regulation of inflammation is modulated by dynamic shifts in metabolism. In macrophages exposed to the bacterial product lipopolysaccharide (LPS), an initial induction of protein biosynthesis is followed by compensatory induction of the transcription factor nuclear factor erythroid 2-like 1 (NRF1), leading to increased flux through the ubiquitin proteasome system (UPS). A major target of NRF1-mediated UPS flux is the mitochondrial proteome, and in the absence of NRF1, ubiquitinated mitochondrial proteins accumulate to trigger severe mitochondrial stress. Such mitochondrial stress engages the integrated stress response-ATF4 axis, which limits mitochondrial translation to attenuate mitochondrial stress but amplifies inflammatory responses to augment susceptibility to septic shock. Therefore, NRF1 mediates a dynamic regulation of mitochondrial proteostasis in inflammatory macrophages that contributes to curbing inflammatory responses.

Keywords: CP: Metabolism; CP: Molecular biology; NRF1; immunometabolism; inflammation; integrated stress response; macrophage; mitochondria; proteostasis.