IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes
| Autor: | Hao Zhou, Wen Qian, Jonathan D. Smith, Ashok Dongre, Xiaoxia Li, Weiwei Liu, Fangqiang Tang, J. Mark Brown, Ruth E. McDowell, Judith A. Drazba, Han Wang, Mei Yin, Christopher Hine, Junjie Zhao, Minjia Yu, Hui Yang, Yeong-Renn Chen, Rebecca C. Schugar, Paul L. Fox, Robert Dent, Ji Gao, Julie Carman |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Immunology Inflammation Oxidative phosphorylation Mitochondrion Oxidative Phosphorylation Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Adipocyte Prohibitins medicine Adipocytes Immunology and Allergy Animals Humans Obesity Beta oxidation Cells Cultured Mice Knockout Kinase Receptors Interleukin-1 Cell biology Protein Transport Oxidative Stress 030104 developmental biology Interleukin-1 Receptor-Associated Kinases chemistry Mitochondrial Membranes Myeloid Differentiation Factor 88 medicine.symptom Signal transduction Cristae formation 030215 immunology Signal Transduction Interleukin-1 |
| Zdroj: | Nature immunology |
| ISSN: | 1529-2916 1529-2908 |
| Popis: | 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. Obesity is often accompanied by chronic inflammation. Li and colleagues show that, in mice fed high-fat diets, IL-1 signaling in adipocytes induces an unconventional IRAK2 translocation to mitochondria and suppresses respiratory super-complex formation to alter mitochondrial function, and exacerbates obesity. |
| Databáze: | OpenAIRE |
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