The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-03-25 Epub Date: 2025-03-06 DOI:10.1016/j.celrep.2025.115403

Jianing Xu, Matthew Wakai, Kun Xiong, Yanfeng Yang, Adithya Prabakaran, Sophia Wu, Diana Ahrens, Maria Del Pilar Molina-Portela, Min Ni, Yu Bai, Tea Shavlakadze, David J Glass

{"title":"The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis.","authors":"Jianing Xu, Matthew Wakai, Kun Xiong, Yanfeng Yang, Adithya Prabakaran, Sophia Wu, Diana Ahrens, Maria Del Pilar Molina-Portela, Min Ni, Yu Bai, Tea Shavlakadze, David J Glass","doi":"10.1016/j.celrep.2025.115403","DOIUrl":null,"url":null,"abstract":"<p><p>Chronic inflammation and a decline in mitochondrial function are hallmarks of aging. Here, we show that the two mechanisms may be linked. We found that interleukin-6 (IL6) suppresses mitochondrial function in settings where PGC1 (both PGC1α and PGC1β) expression is low. This suppression is mediated by the JAK1/STAT1/3 axis, which activates HIF1α through non-canonical mechanisms involving upregulation of HIF1A and ERRα transcription, and subsequent stabilization of the HIF1A protein by ERRα. HIF1α, in turn, inhibits ERRα, which is a master regulator of mitochondrial biogenesis, thus contributing to the inhibition of mitochondrial function. When expressed at higher levels, PGC1 rescues ERRα to boost baseline mitochondrial respiration, including under IL6-treated conditions. Our study suggests that inhibition of the IL6 signaling axis could be a potential treatment for those inflammatory settings where mitochondrial function is compromised.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 3","pages":"115403"},"PeriodicalIF":6.9000,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2025.115403","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/6 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Chronic inflammation and a decline in mitochondrial function are hallmarks of aging. Here, we show that the two mechanisms may be linked. We found that interleukin-6 (IL6) suppresses mitochondrial function in settings where PGC1 (both PGC1α and PGC1β) expression is low. This suppression is mediated by the JAK1/STAT1/3 axis, which activates HIF1α through non-canonical mechanisms involving upregulation of HIF1A and ERRα transcription, and subsequent stabilization of the HIF1A protein by ERRα. HIF1α, in turn, inhibits ERRα, which is a master regulator of mitochondrial biogenesis, thus contributing to the inhibition of mitochondrial function. When expressed at higher levels, PGC1 rescues ERRα to boost baseline mitochondrial respiration, including under IL6-treated conditions. Our study suggests that inhibition of the IL6 signaling axis could be a potential treatment for those inflammatory settings where mitochondrial function is compromised.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

促炎细胞因子IL6通过gp130-JAK1/STAT1/3-HIF1α/ERRα轴抑制线粒体功能。

慢性炎症和线粒体功能下降是衰老的标志。在这里，我们表明这两种机制可能是联系在一起的。我们发现白细胞介素-6 （IL6）在PGC1 （PGC1α和PGC1β）表达低的情况下抑制线粒体功能。这种抑制是由JAK1/STAT1/3轴介导的，它通过非规范机制激活HIF1α，包括HIF1A和ERRα转录的上调，以及随后由ERRα稳定HIF1A蛋白。反过来，HIF1α抑制ERRα， ERRα是线粒体生物发生的主要调节因子，从而有助于抑制线粒体功能。当PGC1在较高水平表达时，PGC1可拯救ERRα以促进基线线粒体呼吸，包括在il - 6治疗的条件下。我们的研究表明，抑制IL6信号轴可能是线粒体功能受损的炎症设置的潜在治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.