IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes

• DOI: 10.1038/s41590-020-0750-1
• Publication Date: 2020-08-10T16:03:30Z
• Authors: Hao Zhou; Han Wang; Minjia Yu; Rebecca C. Schugar; Wen Qian; Fangqiang Tang; Weiwei Liu; Hui Yang; Ruth E. McDowell; Junjie Zhao; Ji Gao; Ashok Dongre; Julie A. Carman; Mei Yin; Judith A. Drazba; Robert Dent; Christopher Hine; Yeong-Renn Chen; Jonathan D. Smith; Paul L. Fox; J. Mark Brown; Xiaoxia Li
• Keywords: Inflammation; Male; Mice, Knockout; 2. Zero hunger; Receptors, Interleukin-1; Article; Oxidative Phosphorylation; Mice; Protein Transport; Interleukin-1 Receptor-Associated Kinases; Mitochondrial Membranes; Myeloid Differentiation Factor 88; Prohibitins; Adipocytes; Animals; Humans; Obesity; Cells, Cultured; Interleukin-1; Signal Transduction

Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.