Emerging role of the itaconate-mediated rescue of cellular metabolic stress

Abstract

Metabolic regulations play vital roles on maintaining the homeostasis of our body. Evidence have suggested that ATF3 and nuclear factor erythroid 2-related factor 2 (NRF2) are critical for maintaining cell function, metabolism, and inflammation/anti-inflammation regulations when cells are under stress, while the upstream regulators in the stressed cells remain elusive. Recent findings have shown that tricarboxylic acid cycle metabolites such as itaconate and succinate are not just mitochondrial metabolites, but rather important signaling mediators, involving in the regulations of metabolism, immune modulation. Itaconate exerts anti-inflammatory role through regulating ATF3 and NRF2 pathways under stressed conditions. In addition, itaconate inhibits succinate dehydrogenase, succinate oxidation and thus blocking succinate-mediated inflammatory processes. These findings suggest itaconate-ATF3 and itaconate-NRF2 axes are well-coordinated machineries that facilitate the rescue against cellular stress. Here, we review these fascinating discoveries, a research field may help the development of more effective therapeutic approach to manage stress-induced inflammation, tissue damage, and metabolic disorder.

Keywords: ATF3; Inflammasome; Itaconate; Mitochondrial stress; Nuclear factor erythroid 2–related factor 2.

Figure 1

Itaconate-induced cell protective anti-stress responses. Inflammatory stimulus such as LPS upregulates the expression of CAD (also known as IRG1), an enzyme converts cis-aconitate to itaconate in the mitochondria [4]. LPS-induced cellular activation leads to glycolytic flux and the transition towards an anaplerotic TCA cycle with high production levels of itaconate [9]. High itaconate levels suppress SDH, blocking succinate-mediated inflammatory processes and inducing the anti-inflammatory proteins NRF2 and cyclic ATF3 [9]. Succinate may enhance proinflammatory cytokine IL-1β pathway through SUCNR1 [3]. Those blue labels indicate the anti-inflammatory and anti-oxidative-stress responses; those red labels indicate proinflammatory responses. LPS: Lipopolysaccharide, CAD: Cis-aconitate decarboxylase, IRG1: Immune-responsive gene 1, SDH: Succinate dehydrogenase, NRF2: Nuclear factor erythroid 2-related factor 2, ARF3: AMP-dependent transcription factor 3, SUCNR1: Succinate receptor 1, IDH: Isocitrate dehydrogenase

Figure 2

The metabolic brake model. Itaconate-mediated regulations (e.g. itaconate-ATF3, itaconate-NRF2 axes) serve as potential “metabolic brakes” to conduct anti-inflammation, anti-oxidant and tissue repair effects. The “metabolic brake” exerts ameliorative roles on metabolic stresses (e.g. oxidative stress, excessive inflammation, metabolic overload, obesity) induced adverse effects. The image of wheel displayed in the center of the figure is originally downloaded (March 19, 2021) from the clipart-library.com, a free cliparts collection. NRF2: Nuclear factor erythroid 2-related factor 2, ARF3: AMP-dependent transcription factor 3